Epigenetics of Aging and Cancer: A Comprehensive Look

Epigenetics of Aging and Cancer: A Comprehensive Look

C H A P T E R 37 Epigenetics of Aging and Cancer: A Comprehensive Look Antja-Voy Hartley1, Matthew Martin1, Jiamin Jin1, and Tao Lu1,2,3 1 Departmen...

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C H A P T E R

37 Epigenetics of Aging and Cancer: A Comprehensive Look Antja-Voy Hartley1, Matthew Martin1, Jiamin Jin1, and Tao Lu1,2,3 1

Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, United States 2 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United States 3 Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States

37.1 INTRODUCTION The aging process is unquestionably complex and universally manifests as a gradual decline of physiological function. Over the past decade there has also been a growing understanding that such physiological changes are accompanied by underlying alterations in cellular epigenetic states. Although population-based longevity studies indicate that genetic factors account for about one-third of differences observed in the life spans of individuals,1 it is now believed that epigenetic drifts have an even more profound influence on the aging process.2–7 By definition, epigenetics represents the reversible heritable changes in gene expression that occur without any alteration of the underlying DNA sequence.8 Strikingly, certain types of epigenetic changes can be passed on to even influence the life span of progeny.2, 9–11 Moreover, many studies suggest that, given the reversible nature of such epigenetic information, previously unexplored and exciting novel avenues for therapeutic intervention in aging and age-associated diseases may become possible.4, 5, 12–15 However, the exact causes of aging remain poorly understood, and continued efforts are under way to delineate aging and longevity cellular pathways conserved among eukaryotes. Epigenetic changes occur at different levels and include mechanisms such as alterations in the patterns of histone posttranslational modifications, noncoding RNA expression, DNA methylation, and chromatin structure accompanied by events like the replacement of canonical histones with histone variants.13, 16–19 The net effect of such epigenetic changes during aging is altered accessibility to genetic material that in turn significantly affects gene expression.7, 13 Over time, these aberrant gene expression changes accumulate, leading to damaging genomic instability, defects in DNA repair, and enhanced susceptibility of the organism to diseases such as cancer, neurodegeneration, diabetes, and cardiovascular disorders.20 It has been well established that aging constitutes a major demographic risk factor for the development of cancer.15, 21, 22 Despite this growing understanding, studies dedicated to elucidating the underlying molecular links between aging and cancer are alarmingly lacking. This chapter explores the great strides that have been made thus far to identify and categorize some of the molecular hallmarks of aging and cancer. Specifically, we highlight recent studies pertaining to the epigenetic alterations behind cancer as well as those contributing to deteriorated cellular functions observed during aging. Moreover, we discuss important insights into the critical role that epigenetic aberrations play as mechanistic links between both processes and, finally, current therapeutic strategies under way that explore this new frontier.

37.2 EPIGENETIC SIGNATURES IN AGING 37.2.1 Changes in DNA Methylation The aging process affects every cell of the body and is marked by distinct epigenetic modifications.16, 20 One of the most characterized epigenetic alterations that occurs during aging pertains to changes in the DNA methylation Pharmacoepigenetics https://doi.org/10.1016/B978-0-12-813939-4.00037-1

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patterns within cells.19, 23, 24 This involves the addition of methyl groups, catalyzed by DNA methyltransferases (DNMTs), to the five position of cytosines located in CpG dinucleotides.19 These CpG dinucleotides account for 2%–5% of the genome and are primarily found in clusters near transcription start sites, also known as CpG islands.19 Over the years the research focused on DNA methylation patterns in aging has rapidly gained momentum as a result of the availability of microarray platforms, like the HumanMethylation27 BeadChip, which has facilitated the simultaneous analysis of more than 27,000 CpG sites.25 In fact, age-specific changes in the DNA methylation pattern at CpG dinucleotides has been detected in a wide array of tissue types and has been shown to be a useful predictor of donor age.24, 26–28 To date, several studies have used this platform to determine age-related DNA methylation changes in various cell types or tissues including mesenchymal stem cells (MSCs), fibroblasts,27, 29 dermis,30 epidermis,30 blood,31 and cervical smears.27–29, 32, 33 Importantly, many of these studies suggest the occurrence of both hypomethylation and hypermethylation ageassociated events at various sites.34–37 For instance, Bocklandt et al.38 showed that hypermethylation of three CpG sites in the promoters of ectodysplasin-A receptor-associated adapter protein (EDARADD), target of Myb-like protein 1 (TOM1L1), and neuronal pentraxin II (NPTX2) genes occurred linearly with age over a range of five decades, all notably known to affect age-related diseases, such as cancer and cardiovascular and neurological abnormalities.38 Of these validated genes, hypermethylation of NPTX2 has been shown to occur in pancreatic cancer while mutations in EDARADD have been linked to loss of hair, sweat glands, and teeth.38 Koch and Wagner28 also used data sets obtained from dermis, epidermis, cervical smears, T cells, and monocytes to identify 19 CpG sites hypermethylated upon aging, among which NPTX2 was once again identified along with genes GRIA2, KCNQ1DN, and TRIM58.27, 28 These, along with an additional hypomethylated CpG site at the BIRC4BP promoter, were applied in a model to predict donor age.28 However, further research to elucidate their exact roles in various age-related phenotypes is warranted. Another independent study analyzing the genome of a population cohort ranging in age from 14 to 94 discovered 476,366 methylation sites within the genome of white blood cells (N ¼ 421). They found that approximately 29% of the sites were methylated with increasing age, of which 60.5% became hypomethylated and 39.5% hypermethylated. Moreover, DNA methylation sites located within CpG islands were more often hypermethylated than non-CpG sites.24 The Rakyan group also identified aging-associated differentially methylated regions (aDMRs) in whole blood in a discovery cohort of which 213 CpG sites became more methylated with age (hyper-aDMRs) and 147 CpG sites became hypomethylated (hypo-aDMRs). Additionally, hyper-aDMRs were found to be strongly enriched for CpG islands and preferentially occurred at bivalent chromatin domains in stem cells of embryonic and hematopoietic origin.34 This is important since aberrant DNA methylation at promoters harboring bivalent chromatin domains has been associated with decreased differentiation capacity and greater proliferation in vitro.34, 39, 40 However, the question remains, how do these DNA methylation patterns subsequently affect gene expression? In this respect, Johansson’s group showed that of the mapped 28,984 probes a much larger fraction of the genes that became hypermethylated with age had decreased expression, whereas a smaller percentage had increased expression with age (2.91%) than the average.24 Interestingly, for genes that became hypomethylated with age, a greater fraction also showed decreased expression, suggesting that both hypermethylation and hypomethylation can result in differential expression, most likely by distinct regulatory mechanisms.24 Taken together, these data highlight the significant role that aberrant DNA methylation plays in the aging process and its potential contribution to a number of age-related diseases. A large fraction of hypermethylated CpG sites in the aged might result in repression of many genes critical to the maintenance of health.14 Therefore, a better understanding of the changes in DNA methylation throughout one’s life span might lead to improved preventive and therapeutic strategies for these diseases.13, 41

37.2.2 Changes in Histone Posttranslational Modifications Histones are subject to a wide array of posttranslational modifications (PTMs).42, 43 These PTMs serve to disrupt or recruit other proteins to specific regions of the chromatin, thereby determining transcription of the underlying DNA sequence.42, 44 Given the critical roles they play in orchestrating the diverse functional responses of the cell, these marks, which vary both in type and site, are highly complex and tightly regulated.45, 46 Of the histone modifications known to be involved in the aging process, lysine acetylation and methylation are the most prominent.13, 43 For instance, in yeast the acetylation of histone H3 on lysine 56 (H3K56Ac) and histone H4 on lysine 16 (H4K16Ac) both influence replicative aging.42, 47 Changes in the optimal levels of acetylation of these residues, as a result of the presence of mutations or deletion of genes encoding epigenetic modifiers, has been shown to correlate with the differential replicative life span of budding yeast.48 For example, too little H3K56Ac and increased levels of H4K16Ac during yeast replicative aging shortens life span.42, 49 In the case of H4K16Ac marks, overexpression of the relevant HDAC Sir2 has

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been shown to extend life span.47, 50–52 Likewise, deletion of SAS2 which encodes the HAT that mediates acetylation of H4K16 promotes longevity.53, 54 Moreover, similar changes in the levels of these two histone acetylation marks also occur during replicative aging of human fibroblasts, wherein a substantial decrease and increase in H3K56Ac and H4K16Ac, respectively, has been observed in late-passage cells.55–57 Other HATs and HDACs that have also been implicated in aging include NuA4 (HAT) and Rpd3 (HDAC), the deletion of which extends the replicative life span of yeast and organismal life span of flies, respectively.58–61 Although the exact underlying mechanisms are not yet clear, the proaging influence of H4K16Ac accumulation and H3K56Ac depletion has been suggested to be implicated in chromatin assembly at telomeres, transcriptional regulation of genes involved in genomic stability, and DNA replication.57, 62 Therefore, any of these functions may contribute to promoting or attenuating longevity, and studies to fully understand the molecular mechanisms utilized by HATs and HDACs warrant further investigation. Recently, the levels of histone methylation during aging have also been extensively examined. For instance, H3K4me3, H3K9me2, H3K9me3, H3K27me3, and H3K36me3 levels have been shown to undergo significant changes.42, 57, 63 A decreased level of H3K9me2 was observed in aging whole flies, whereas an increase in the level of H3K9me3 was observed in fly heads, indicating a tissue-specific pattern for these changes.64–66 Furthermore, on a global level there is an overall increase in the presence of activating histone methylation marks and a concurrent disappearance of repressive ones, signifying the loss of compact chromatin in aging cells.13, 64 Recently, several mechanistic insights into the role of histone methylation during aging have emerged. Tissue from a progeria mouse model showed increased levels of H3K9me3 and the relevant methyltransferase SUV39H1.67 This was accompanied by defective DNA repair processes, possibly due to increased H3K9me3 levels, a hindrance of heterochromatin remodeling, and subsequent continuous DNA damage and shortened life span. The same study also showed that depletion of SUV39H1 rescued this defect, leading to an extended life span.67 In addition to acetylation and methylation, histone ubiquitination is another modification that has been implicated in aging, whereby yeast strains lacking components of the deubiquinase module (DUBm) showed marked life span extension.52 Indeed, future studies will be needed to shed light on the role of histone ubiquitination in aging multicellular organisms as well.

37.2.3 Changes in Noncoding RNAs (ncRNAs) Noncoding RNAs (ncRNAs) have been widely studied in aging, particularly microRNAs (miRNAs) and long noncoding RNAs (lncRNAs).68 lncRNAs are transcripts of 200 nucleotides or greater in length that are not translated into protein, representing the vast majority of ncRNAs.68, 69 This rather arbitrary nucleotide limit distinguishes them from their counterparts microRNAs (miRNAs), a significant class of small noncoding RNAs (sncRNAs) transcribed as 70 nucleotide precursors processed by the enzyme Dicer to yield products with 18–25 nucleotides.70 In general, the function of ncRNAs relates to their ability to regulate gene expression both transcriptionally and posttranscriptionally, affecting a wide range of critical cellular functions including translation, splicing, DNA replication, and the maintenance of chromatin structure.70 It is therefore not surprising that disruption of ncRNA function has been implicated in multiple diseases including age-associated diseases, such as cancer, neurodegeneration, and cardiovascular dysfunction.70–73 During the aging of mice, numerous studies have validated a strong link between reduced Dicer mRNA or protein levels and tissue aging.74 Dicer is a key component of the miRNA machinery and its dysregulation correlates with defective processing of sncRNA, including the expression of miRNAs.75–77 Dysregulation of Dicer in aging rats has been found to affect the angiogenic miRNA signature in cerebromicrovascular endothelial cells and to play a causal role in age-related angiogenesis impairment.78 So far, over 2600 miRNAs have been identified in human cells, many of which are significantly downregulated with age and have also been implicated in modulating tissue aging and life span.79, 80 One of the most prominent examples is lin-4 and its target lin-14 in Caenorhabditis elegans. Loss of function of lin-4 correlated with a shorter life span, whereas overexpression of lin-4 had the opposite effect. Importantly, the targets of these miRNAs were also differentially expressed, with some having an anti-aging effect while others had pro-aging consequences.80–83 However, not all miRNAs are reduced in aging, as many upregulated miRNAs have been found to either promote or inhibit longevity.80, 83 miR-34, for instance, has been shown to be enriched in aged brains obtained from Alzheimer’s disease mouse model brains and samples collected from Alzheimer’s disease patients.84 In this work the authors report that miR-34 may also potentially contribute to age-associated neurodegeneration, but further studies are needed to validate the key protective factors that are downregulated by this miRNA.84 Another report revealed that upregulation

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of miR-71 or miR-246 was shown to promote longevity in C. elegans during aging, whereas miR-239 and miR-34 inhibited life span.83, 85 Notably, two miRNAs with dynamic changes in expression with aging, let-7 and mir-34, are known to be involved in cancer, providing a putative link between miRNAs, life span, and age-related cancer susceptibility.86, 87 Other recent reports have also implicated let-7 in aging-induced senescence in mouse neuronal stem cells.79, 88, 89 Collectively, these data suggest the role of dysregulated miRNA expression as a potential underlying common mechanism in the development of several age-related diseases. When it comes to aging, lncRNAs are far less studied than miRNAs, yet they affect a diverse array of biological processes via the regulation of mRNA stability, chromatin structure, RNA splicing, or by acting as miRNA sponges.69 Kour et al.70 defined several subclasses of lncRNAs involved in the regulation of aging (namely, natural antisense senescence-associated lncRNAs,90 pseudogene-encoded senescence-associated lncRNAs, telomere-associated lncRNAs, chromatin-modulating lncRNAs, and p53-associated lncRNAs).70 Natural antisense transcripts (NATs) are a class of endogenous lncRNAs that act in cis (similar loci) or trans (different loci) to regulate mRNAs encoding proteins involved in various biological processes, including genetic imprinting, splicing, and RNA interference.70 Approximately 27 NATs have been found to be differentially expressed in proliferating versus senescent (S) cells.90 Of these senescence-associated NATs, around half were highly upregulated in proliferating cells when compared with senescent cells.90 However, the molecular basis of the relationship between upregulation of these NATs and the onset of cellular senescence needs further exploration. Pseudogene-encoded transcripts, another subclass of lncRNAs, function by acting as sinks for miRNAs. Recent studies highlighting differential expression of these lncRNAs identified several transcripts that were highly expressed in tumor cells but downregulated in senescent cells.70, 90 Interestingly, some pseudogene-encoded lncRNAs have been shown to alter the expression of various cell adhesion molecules which could potentially impact growth and division to ultimately drive the onset of aging and senescence.70 TERC is an example of a telomerase-associated lncRNA that functions as a template during polymerization of a telomere at chromosomal ends.70, 91 It acts as a critical element for maintaining telomeric integrity, and thus its implication in aging is likely due to the progressive loss of telomerase activity.91 Studies have shown that reexpression of TERC in the germlines of telomerase-deficient mice was sufficient to restore telomere length resulting in protection from chromosomal instability, including end-to-end fusion and chromosomal breaks in subsequent progenies.70, 91 Furthermore, TERC has been implicated in premature aging and its related diseases, like testicular atrophy.70, 92 Overall, these studies emphasize the direct involvement of TERC in regulating cellular senescence and organismal aging. The final two subclasses that are discussed here (namely, chromatin-modulating lncRNAs and p53-associated lncRNAs) have also been implicated in age-related physiological changes and diseases.70 For example, lncRNAs reported to execute their cellular functions via modulating chromatin structure and function generally act as scaffolds via direct or indirect association with chromatin-modifying factors.93–95 Not surprisingly, aberrant levels of expression of these lncRNAs results in many defects in chromatin architecture.70 However, the precise role of chromatinassociated lncRNAs in cellular senescence and aging has not been explored, although they may be implicated in the aging process via their involvement in cell cycle and apoptosis pathways.70 These include such well-known lncRNAs as H19, Kcnq1ot1, HOTAIR, Airn, and ANRIL.96–101 p21-associated ncRNA DNA-damage activated (PANDA) is a well-studied example of p53-associated lncRNAs. It is a bidirectional lncRNA regulated by p53 and is induced upon DNA damage which results in cellular senescence and apoptosis in human fetal lung fibroblasts.102 Puvvula et al.102 showed that differential expression of PANDA determines the entry and exit from senescence, particularly as a result of its regulation of the expression of various prosenescence genes, like CDKN1A.102 Moreover, this study also revealed that low levels of PANDA led to the NF-Y-mediated activation of proliferative genes, including transcription factor E2F, thus sustaining a proliferative state while inhibiting senescence in these fibroblast cells.102

37.3 EPIGENETIC SIGNATURES IN CANCER 37.3.1 Changes in DNA Methylation Over the past decade or so the advent of widespread cancer epigenomic databases has made it possible to identify numerous distinct epigenetic signatures in cancer. Interestingly, several findings have demonstrated that not only do cancer cells harbor specific “epigenetic signatures” unique to cancer type, but that these signatures may also be potentially exploited for the prevention, diagnosis, and treatment of such cancers.103–109 DNA methylation is perhaps the most widely studied epigenetic mechanism involved in cancer.110, 111 The consensus derived from several studies is that while tumor cells typically exhibit a global loss of 5-methyl-cytosine leading to

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an overall hypomethylated state,112 CpG islands tend to be hypermethylated.113–117 The downstream consequences on gene expression, however, seemingly occur in a promoter-targeted fashion. For example, hypomethylation usually affects promoters of genes that become derepressed during tumorigenesis, like certain oncogenes.118, 119 Hypermethylation, on the other hand, tends to affect promoters of tumor suppressor and DNA repair genes, leading to a decrease in their expression even in the absence of mutations.120–124 More recently, researchers have begun to identify certain tumor DNA methylation signatures that differentiate them from the surrounding normal tissue, as well as from other tumor subtypes.104, 125 For instance, Hawes et al.126 reported that DNA hypermethylation was detected in 91% of nonsmall-cell lung cancer (NSCLC) cases and was detected more frequently at genes APC, RUNX, CCND2, and KCNH5 in adenocarcinomas than squamous cell carcinomas (SCCs).126 Interestingly, these DNA methylation patterns also varied substantially by gender where hypermethylation of KCNH5, KCNH8, and RARB occurred more frequently in females than males.126 Another study showed DNA methylation signatures as being useful for breast cancer classification, staging, and prognosis.127 Although many methylation changes have been described, one challenge remains in the field; how do we determine which DNA hypermethylation events in cancer are in fact tumor-driving events? Interestingly, recent evidence suggests that aberrant DNA methylation changes at specific sites in the genome, also known as “epimutations,” can mimic somatic mutations thereby contributing to malignant transformation.128 For example, hypermethylation in typical tumor suppressor genes, such as p21WAF1/CIP1, p16INK4a, RUNX3, RAS association domain family 1A (RASSF1A), and retinoic acid receptor β (RARβ), are frequently observed, leading to their inactivation, subsequent genetic instability, and cancer development.129 Methylation and subsequent silencing of other critical tumor suppressors, such as APC in colorectal cancer and DAP-kinase in gastric cancer, have also been shown to occur in aged patients and act as an important contributor to the development of cancer.130 Conversely, certain hypomethylation signatures have been used to predict poor prognoses, like the hypomethylation of oncogenes in ovarian carcinomas and T cell lymphomas.112, 129, 131 It is not surprising that several members of the major class of enzymes responsible for transferring methyl groups, DNMTs, are themselves frequently deregulated in cancer.112, 129 In acute myeloid leukemia patients a high frequency of missense mutations occurs in the DNMT3A gene and is associated with not only adverse outcomes among these patients but also promotes chemotherapeutic resistance.132–135 Thus AML patients with DNMT3A mutations acquire DNA methylation aberrations although no clear and common epigenetic signature has so far been evidenced.136

37.3.2 Changes in Histone Posttranslational Modifications Global alterations in the patterns of histone PTMs have been extensively linked to cancer.137, 138 It is generally accepted that the sum of all these PTMs largely determines the chromatin structure and hence cellular fate.139 Altered global levels of histone acetylation and methylation, such as a global loss of H4K16ac and H4K20me3, constitute a hallmark of almost all human cancers and has even been found to be of potential prognostic value.140 Moreover, hyperacetylation of protooncogenes leads to activation of their expression, whereas hypoacetylation often localizes to promoters of tumor suppressors.141, 142 In breast cancer cells low H3K4me2 and H3K9ac levels have been observed, whereas lung cancer cells demonstrated low H3K4me2 but high H3K9ac levels.137, 143, 144 Chen et al.145 also showed a correlation between progressed tumor stage and perineural invasion and low H3K4ac/high H3K27me3 levels, further reinforcing the critical role of aberrant histone modifications in cancer progression.145 Importantly, inappropriate expression and/or mutations of histone-modifying enzymes, such as histone deacetylases (HDACs), histone acetyltransferases (HATs), histone methyltransferases (HMTs), and histone demethylases (HDMs), are often responsible for the aberrant histone modifications observed in cancer.137 HDACs, for example, are often found to be elevated in several cancers, including prostate and gastric cancers,146, 147 while aberrant fusion proteins formed by chromosomal translocations of HAT and HAT-related genes (e.g., CBP, MORF, and p300) frequently occur in leukemia.148 Deregulation of HMTs or HDMs in cancer cells also contributes to aberrant histone modification patterns.137 For instance, loss of EZH2, a H3K27-specific methyltransferase, was associated with increased T cell leukemia occurrence in mice.149 In contrast, EZH2 overexpression in prostate, breast, bladder, and endometrial cancers was shown to correlate with increased aggressiveness and disease progression.150–152 Many other HMTs are overexpressed in cancer, including G9a, a H3K9-specific HMT found to promote lung cancer invasion and metastasis by silencing E-CAM.153 More recently, protein arginine methyltransferases (PRMTs) have also emerged as crucial players in a wide array of cancers of which PRMT5 has received most attention as a result of the strong correlation between its frequent upregulation and poor patient prognosis, suggesting that these enzymes could constitute promising targets for cancer therapy.154, 155 Furthermore, recent studies have even shown that prostate cancer

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subtypes can be classified by patterns of H4K20me1, me2, and me3.137 Finally, another class of epigenetic enzymes, the demethylases (e.g., LSD1 or KDM1A) were found to be involved in maintaining the undifferentiated, malignant phenotype of cancer cells, like neuroblastoma cells.156 In summary, these studies strongly support the significant role that histone modification imbalances play in tumorigenesis and cancer progression. It is still moot, however, whether these imbalances are merely consequences or direct drivers of carcinogenesis and hence further studies are needed to develop these ideas fully.

37.3.3 Changes in Noncoding RNAs (ncRNAs) In addition to the role they play in aging, ncRNAs are also important modifiers of the translational and transcriptional processes involved in cancer69, 157, 158 (specifically, various studies have shown that aberrant expression of miRNAs in cancer cells lines and patient samples compared with their normal counterparts may contribute to both the onset of cancer as well as poor prognosis of various neoplasms69). The earliest evidence of miRNA involvement in human cancer identified miR-15a and miR-16-1 as important tumor suppressors in B cell chronic lymphocytic leukemia patients via repression of Bcl-2, an antiapoptotic protein overexpressed in many solid malignancies.87, 159, 160 Furthermore, decreased expression of let-7 has been repeatedly associated with increased malignancy in a variety of cancers, whereas ectopic expression of let-7 inhibits proliferation of tumor cells both in vivo and in vitro.161, 162 In a study by Zhao et al.163 specific members of the let-7 family were observed to be downregulated in breast cancer cells.163 Importantly, its downregulation was found to be inversely correlated with the expression of ERα, suggesting a mechanistic role for let-7 in ER-positive MCF-7 breast cancer cells.163 It is important to note, however, that the role of miRNAs in cancer occurs in a tissue-specific manner. For example, in breast cancer miR-200 has been shown to exert an oncogenic role, whereas in ovarian, renal, and lung tumors loss of miR-200 family members significantly correlated with poor overall survival.87, 164 Like miRNAs, numerous additional studies have reported cancer-associated lncRNAs. A recent study revealed that lncRNA Low Expression in Tumor (lncRNA-LET) transcripts were found to be significantly reduced in several tumor tissues compared with their paired nontumor tissues, including carcinomas of the liver, lung, and colon.165 Moreover, this downregulation of lncRNA-LET was mediated by histone deacetylase 3 (HDAC3) and stabilization of the nuclear factor 90 protein (NF90) in a hypoxia-induced manner, illustrating that lncRNA-LET could be a key regulator of hypoxia signaling in tumor cells.166 On the other hand, ectopic expression of lncRNA-LET attenuated the formation of tumor metastases in a mouse xenograft model.166 Other well-studied lncRNAs include HULC, a highly expressed transcript in HCC and colorectal carcinomas, which has been shown to contribute to liver metastasis by sponging miR372.167, 168 Oncogenic lncRNA PVT1 is upregulated by MYC in transformed cells and its inhibition is correlated with decreased proliferation and increased apoptosis of breast and ovarian cancer cell lines.169 In addition, high levels of PVT1 were associated with poor survival in these and other patients, such as those with various gastrointestinal cancers.169, 170 Essentially, these studies highlight that dysregulation of miRNAs and lncRNAs represent a crucial protumorigenic mechanism. In fact, clinical trials utilizing miRNA profiling for patient prognosis and treatment response are now under way, with several miRNA mimics having been approved for clinical use since 2013.171, 172

37.4 EPIGENETIC CHANGES LINKING AGING AND CANCER 37.4.1 DNA Methylation It is well known that aging, which is associated with highly reproducible DNA methylation changes, may contribute to higher prevalence of malignant diseases, like cancer, in the elderly. Importantly, global DNA hypermethylation and DNA hypomethylation occur in both tumorigenesis and age-related senescence, suggesting an epigenetic link between the two processes.16, 33, 116, 129, 173 Additionally, more “targeted” hypermethylation events also occur in the promoters of certain tumor suppressor genes, such as LOX, p16, RUNX3, and TIG1, which are frequently observed in normal cells as age increases and may contribute to tumor susceptibility in aging populations.174, 175 Furthermore, several studies in which the authors analyzed epigenetic aging signatures in the DNA methylation profiles of various cancer types from The Cancer Genome Atlas (TCGA) demonstrate significant overlap between age-associated DNA methylation patterns and those relevant for cancer development.175 For example, Lin and Wagner176 showed that certain age-associated DNA methylation events in cancer tissues were seemingly accelerated when compared with matched normal tissues.176 DNA methylation levels were increased across many cancer tissue types compared with

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normal tissues. This was particularly observed in CpG sites with age-associated hypermethylation, but not for those with age-associated hypomethylation.176 It is important to note that aberrant hypermethylation at DNA methyltransferase 3A (DNMT3A) may contribute to the initiation of acute myeloid leukemia (AML) and has been observed in AML samples with significantly more age-associated DNA methylation changes.177 These data support the notion that DNA methylation changes appear to be coordinated within cancer samples, particularly at age-associated hypermethylation CpGs, and are not randomly affected.176 Notably, based on epigenetic signatures for age estimations, tumor cells are often predicted to be much older than the chronological age of the patient and may be an important prognostic indicator.176 For instance, stratification of the DNAm profiles of thyroid carcinoma (THCA) and renal clear cell carcinoma (KIRC) by mean age predictions showed that tumors with younger epigenetic age predictions were associated with better prognosis.176 Aging is associated with highly reproducible DNA methylation (DNAm) changes, which may contribute to higher prevalence of malignant diseases in the elderly. In this study, we analyzed epigenetic aging signatures in 5,621 DNAm profiles of 25 cancer types from The Cancer Genome Atlas (TCGA). Overall, age-associated DNAm patterns hardly reflect chronological age of cancer patients, but they are coherently modified in a nonstochastic manner, particularly at CpGs that become hypermethylated upon aging in nonmalignant tissues. This coordinated regulation in epigenetic aging signatures can therefore be used for aberrant epigenetic age-predictions, which facilitate disease stratification. For example, in acute myeloid leukemia (AML) higher epigenetic age-predictions are associated with increased incidence of mutations in RUNX1, WT1, and IDH2, whereas mutations in TET2, TP53, and PML-PARA translocation are more frequent in younger age-predictions. Furthermore, epigenetic aging signatures correlate with overall survival in several types of cancer (such as lower grade glioma, glioblastoma multiforme, esophageal carcinoma, chromophobe renal cell carcinoma, cutaneous melanoma, lung squamous cell carcinoma, and neuroendocrine neoplasms). In conclusion, age-associated DNAm patterns in cancer are not related to chronological age of the patient, but they are coordinately regulated, particularly at CpGs that become hypermethylated in normal aging. Furthermore, the apparent epigenetic age-predictions correlate with clinical parameters and overall survival in several types of cancer, indicating that regulation of DNAm patterns in age-associated CpGs is relevant for cancer development. Although hypermethylation and hypomethylation changes occur in both cancer and aging, some studies suggest that these methylation changes may not necessarily correlate bidirectionally in both processes. For instance, DNA methylation patterns associate with different chromatin contexts during aging and tumorigenesis.178–180 During tumorigenesis, DNA hypomethylation arises in heterochromatin displaying the repressive H3K9me3 modification, affecting genes associated with cellular signaling. However, no strong correlations with hypomethylated regions in aging have been observed. Instead, DNA hypomethylated sequences were enriched at genomic regions marked with the activating histone posttranslational modification H3K4me1 in aging.181 Conversely, hypermethylated regions associate with both aging and tumorigenesis and display similar chromatin modifications characteristic of “bivalent chromatin domains.”181 These domains consist of the repressive histone mark H3K27me3 and the active mark H3K4me3.181, 182 Overall, the genes affected by this process, such as EZH2 and components of the SUZ12 polycomb complex, are associated with development, supporting a putative stem cell origin of cancer whereby aberrant hypermethylation could regulate genes that promote a prolonged self-renewing state in cancer cells.33, 181 Moreover, the preferential hypermethylation in aging and cancer of genes harboring these bivalent chromatin marks suggests in part that this might be an instructive process related to epigenetic stem cell memory.183 This flawed hypermethylation process appears to occur during normal aging, thereby contributing to predisposition to cancer in the elderly.183 Taken together, these reports demonstrate that, while hypermethylation and hypomethylation changes serve as a critical link between aging and cancer, further studies are needed to elucidate the potential differential underlying mechanisms at play (Fig. 37.1).

37.4.2 ncRNAs ncRNAs continue to serve as important regulators of transcription through their interaction with chromatin or chromatin-associated factors and thus directly or indirectly act as critical modulators of both aging and cancer processes.157 For instance, loss of imprinting at lncRNA H19, a differentially spliced product of the H19 gene located at the IGF2/H19 imprinted locus, has been shown to occur during aging in both mice and human prostates.191 Loss of imprinting, which led to an elevated expression of H19 and IGF2, is linked to both aging and cancer and potentially serves as a reason for increased prostate cancer occurrence in aging men.191 H19 is also highly expressed in low-grade bladder carcinoma patients, suggesting that H19 can be used as an early marker for recurrence of metastatic bladder cancer.192 In breast cancer, MYC, which is involved in cancer-associated senescence, binds to the H19 promoter to

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FIG. 37.1

Epigenetic factors linking aging and cancer. A model depicting the many epigenetic factors proposed to contribute to age-associated increase in cancer incidence. These include mechanisms such as alterations in the patterns of1 histone posttranslational modifications which are characterized by global methylation and acetylation aberrations2; altered noncoding RNA expression, including miRNAs, lncRNAs, and their targets3; aberrant DNA methylation (specifically, hypermethylation of CpG sites and bivalent covalent domains) leading to stable gene silencing in aged and cancer cells; and4 defects in chromatin structure due to mutations that result in loss or gain of chromatin remodeler function.13, 16–19 The net effect of such epigenetic changes during aging is altered accessibility to genetic material, and this in turn significantly affects gene expression.7, 13 Over time these aberrant gene expression changes accumulate, leading to damaging genomic instability, defects in DNA repair, and enhanced susceptibility of the organism to diseases like cancer.20 Furthermore, current therapeutic agents targeting these epigenetic modifications in cancer and other ageassociated diseases have gained traction as viable treatment options for patients with certain blood and solid cancers. As portrayed, these agents include broad reprogrammers, such as HDAC inhibitors (HDACi), DNMT inhibitors (DNMTi), as well as more targeted inhibitors against specific HMTs (e.g., EZH2).184–189 Finally, the use of specific miRNA mimics in cancer have also met with some success.190 DNA, Deoxyribonucleic acid; DNMT, DNA methyltransferase; HDAC, histone deacetylase; HMT, histone methyltransferase; lncRNA, long noncoding RNA; miRNA, microRNA.

facilitate histone acetylation and transcriptional initiation.193, 194 Furthermore, H19 and miR-675, the miRNA it harbors, are upregulated in human colorectal cancer cell lines and primary cells.195 Upregulation of miR-675 lowered expression of the tumor suppressor pRB (retinoblastoma protein), while inhibition reduced colon cancer cell growth and colony formation.196 Many ncRNAs implicated in cancer have also been directly or indirectly associated with age-related processes, such as senescence and autophagy. Here, we highlight a few relevant lncRNAs. Chongtae Kim and colleagues reported that 7SL, an lncRNA that is highly expressed in several cancers, acts to suppress TP53 translation via competitive binding to TP53 mRNA and thus promotes tumorigenesis by silencing this major tumor-suppressing pathway.197 Furthermore, although its impact on aging has not been studied directly, depletion of 7SL has been found to promote autophagy and senescence, two major hallmarks of aging and growth suppression.197 Another ncRNA MALAT1 was downregulated in senescent cells, which significantly enhanced TP53 expression.198–200 Similar to 7SL, the notion that MALAT1 also acts as a critical modulator of tumorigenesis is supported by its overexpression in several cancers, including lung and liver carcinoma.201, 202 Other ncRNAs have been implicated in both cancer and age-associated senescence, including Hox antisense intergenic RNA (HOTAIR) that plays a significant role in regulating gene expression related to cell proliferation, senescence,

37.4 EPIGENETIC CHANGES LINKING AGING AND CANCER

TABLE 37.1

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Comparison of Epigenetic Signatures in Aging and Cancer

and cancer by modulating and recruiting chromatin modifiers, like PRC2, thus altering H3K27me3 marks.203 Furthermore, high HOTAIR levels are associated with poor prognosis in breast, colorectal, cervical, and endometrial cancer.204 ANRIL, another ncRNA identified in a GWAS study as a risk locus for several cancers, was found to be upregulated in cancers, such as breast and nonsmall-cell lung carcinomas. Importantly, ANRIL also inhibited senescence by repressing transcription of the tumor suppressor gene p15 (INK4B).203, 205 Additionally, ANRIL promoted tumor growth by blocking the actions of miR-99a, a miRNA that inhibits HCC cell proliferation, and miR-449a, which induces prostate cancer cell cycle arrest and senescence.73, 206 Other age- and cancer-associated ncRNAs have been reported, like BCYRN1, which is highly expressed in cancers of the breast, cervix, esophagus, lung, ovary, parotid, and tongue.73 BCYRN1 has been found to be highly enriched in AD brains compared with age-matched normal brains, suggesting its role in both age-associated cancer and neurodegeneration.207 Finally, lncRNA XIST (X inactive-specific transcript), which is frequently downregulated in senescent cells and upregulated in breast cancer, also correlated with taxol sensitivity and chemotherapeutic resistance in ovarian cancers.73, 208 Taken together, these data provide collective evidence that ncRNAs act as an important epigenetic link between aging and age-associated cancer development, likely by modulating senescence and proliferation pathways (Table 37.1).

37.4.3 Chromatin Structure and Remodeling Chromatin is made up of nucleosomes, repetitive units of 146 bp of DNA tightly wrapped around an octameric core of histone proteins (H2A, H2B, H3, and H4).209 Nucleosomes are then further packaged into higher order structures, a process determined by ATP-dependent remodeling proteins as well as the methylation status of the DNA itself.210 Importantly, the level of chromatin compaction and hence the accessibility of DNA and recruitment of chromatinassociated factors determine the outcome of transcription. For example, euchromatin, which is loosely packed and generally transcriptionally active, stands in contrast to heterochromatin, which is more compacted and generally represents a transcriptionally repressive state.211 Although the functional relevance of age-associated epigenetic changes remains to be elucidated, their genomewide occurrence and high reproducibility suggest that they likely influence chromatin organization thereby favoring acquisition of aberrant transcriptional changes contributing to cancer in the aged.39, 173, 177, 180, 183 As previously mentioned, the regulation of nucleosome architecture during different biological events is mediated primarily by adenosine 50 -triphosphate (ATP)-dependent nucleosome-remodeling complexes.13 These complexes utilize the energy of

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37. EPIGENETICS OF AGING AND CANCER: A COMPREHENSIVE LOOK

ATP hydrolysis to package, expel, or slide nucleosomes in a highly regulated manner.13 Importantly, mutations that result in the loss or gain of these remodelers’ functions have been linked to both physiological aging and cancer. In both processes, signs of extensive alterations to chromatin structure are evident, typically followed by increased susceptibility to persistent DNA damage.13 The first evidence pointing to a putative link between chromatin architecture and aging came from Saccharomyces cerevisiae studies in which Sir2 histone deacetylase was found to be important for establishing heterochromatin at telomeres and ribosomal DNA (rDNA).212, 213 Upon aging, repetitive rDNA tended to hyperrecombine and form extrachromosomal rDNA circles, indicative of increased chromatin fragility. Overexpression of Sir2 resulted in the formation of heterochromatin at rDNA sites by reducing this hyperrecombination and thus served to prolong life span.214 Furthermore, recent analysis of chromatin defects in the premature aging disease Hutchinson–Gilford progeria syndrome (HGPS) have also given some preliminary insights into the molecular mechanisms leading to chromatin defects in aging. HGPS is an extremely rare autosomal-dominant genetic disorder with symptoms resembling aspects of aging. Caused by a de novo point mutation in the lamin A gene that results in a truncated form of lamin A (progerin), HGPS is characterized by pronounced chromatin defects.215, 216 Notably, further analysis revealed that chromatin defects in HGPS are due to actions of the NURD complex that consists of the histone deacetylases HDAC1 and HDAC2 and the ATPases CHD3 and CHD4.217 Reduction or knockdown of the protein levels and activity of various NURD components, including HDAC1 in HGPS cells and cells from elderly normal human subjects, uncovered a role for NURD loss in aging-associated chromatin defects, including histone demethylation, heterochromatin loss, and increased DNA damage.13, 217 Evidence also suggests that age-associated perturbations in chromatin structure contribute to increases in cancer incidence. Interestingly, it appears that depending on the state of the chromatin a cancer-suppressing or cancer-promoting effect may be achieved, also inextricably linked to aging.13 For instance, while age-associated programmed changes in chromatin structure can halt the development of cancer in cells via activation of senescence or apoptosis processes, unprogrammed, inappropriate age-associated chromatin changes may themselves be major underpinnings for tumorigenesis.183, 218 These signals converge on pathways, such as the p53 and p16INK4a-pRB tumor suppressor pathways, which impart a marked reorganization of chromatin structure.183 In cells expressing p16INK4a, for example, ageassociated senescence is induced upon localization of the histone variant H2AZ to a chromatin boundary that prevents heterochromatin from silencing the p16INK4a gene.219 However, depleted expression of p16INK4a is associated with a loss of this boundary in breast cancer cells, thus facilitating their evasion of the senescence process.219 Notably, EZH2, a histone methyltransferase and member of the PRC2 polycomb repressor complex, generates H3K27Me3 to silence expression of p16INK4a in transformed cells, while in aged senescent cells polycomb-mediated repression is relieved via downregulation of EZH2 and is replaced by activators of transcription.220, 221 Thus the EZH2-p16INK4a axis acts as a barrier to cancer by promoting senescence in response to age-associated cellular damage. Taken together, these reports underscore the complex and highly sophisticated interplay between aging and cancer, suggesting the need for more studies to elucidate the epigenetic mechanisms that suppress or promote the onset of age-related cancer.

37.5 THERAPEUTIC TARGETS AND CURRENT PHARMACOEPIGENETIC-BASED STRATEGIES FOR AGING AND CANCER 37.5.1 Pharmacoepigenetic-Based Therapies in Cancer Collectively, several findings emphasize the need for targeting epigenetic changes as novel therapeutic strategies for treating age-associated diseases like cancer. The current therapeutic agents targeting epigenetic modifications roughly fit into two major categories: broad reprogrammers of the epigenome and targeted agents. Broad reprogrammers are comprised of DNA methyltransferase inhibitors (DNMTi), histone deacetylase inhibitors (HDACi), and inhibitors of the bromodomain and extraterminal motif proteins (iBETs).184 Pan-DNMTi, such as azacitidine and decitiabine, have proven somewhat effective for the treatment of myelodysplastic syndrome and AML.185 Unfortunately, their limited use and efficacy as a result of the development of therapeutic resistance have been a major hurdle in the clinic.185–187 HDACi have also been used with relative success for the treatment of lymphomas, including vorinostat, an HDAC class I, II, and IV inhibitor, and romidepsin, a class I inhibitor.188 Other inhibitors, such as iBETs, have been developed to target BRD4, which is critical to reading an acetylated histone signal that induces expression of oncoproteins including MYC.189 Currently, although many iBETs have made it to the clinical trial phase, they are yet to be approved for patient use. In addition to these broad inhibitors, more targeted agents, like specific miRNA mimics in cancer, have also met with some success. MRX34, the first miRNA-based therapy specifically for cancer, is a nanoparticle-based synthetic miR-34a. Normally, miR-34a acts as a tumor suppressor downstream of p53 and its expression is frequently lost in

37.6 PERSPECTIVES

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cancer.222 MRX34 therefore acts to antagonize key cancer hallmarks including the self-renewing and migratory potential of cancer cells.190 Certain other targeted therapies have also been used with success in lymphomas, like the EZH2 inhibitor tazemetostat, which blocks H3K27me3 marks and is currently in phase II clinical trials.223 Other examples of targeted agents include inhibitors AG-881 and AG-120 which target IDH, a class of αKG-dependent enzymes involved in modulating chromatin structure, DNA/RNA methylation, and cellular signaling. Some patients carrying gain-of-function mutations in the IDH1/2 gene have benefited from these inhibitors, which are currently in phase II clinical trials for the treatment of AML.224 However, despite the promise shown by these agents, individual responses, particularly to broad reprogrammers, has proven to be highly variable, and therapeutic resistance often develops in patients.184, 188 Furthermore, even for targeted agents, like miRNA mimics, the development of therapeutic resistance continues to be a major challenge that may be overcome by the use of combinatorial therapies.225 Nonetheless, many epigenetic-based therapies, like miRNA mimics, are still in their infancy and approaches to circumvent potential side effects need further development.

37.5.2 Pharmacoepigenetic-Based Aging Therapies Although aging is a natural phenomenon common to all living organisms, some scientists propose that hallmarks of the aging process could be potentially postponed or prevented by certain approaches. Besides cancer, several drugs targeting HDACs have recently been recommended for the treatment of age-associated diseases.226 Chiefly, high hopes have been placed on the therapeutic potential of drugs targeting NAD-dependent class III HDACs or sirtuins as an attractive novel therapeutic strategy for age-associated diseases, such as diabetes and cardiovascular and neurodegenerative disorders.50, 227 Sirtuins deacetylate both histone and nonhistone substrates, and their activity has been shown to be modulated by dietary and exercise-related nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide dehydrogenase, thereby linking epigenetic changes to environmental interventions that may delay aging.228 Moreover, selective inhibition of SIRT2 using AGK-2 has been reported to have protective effects against Parkinson’s disease,229 whereas sirtuin activators, like resveratrol, have been indicated in the treatment of Alzheimer’s disease and diabetes.230–232

37.6 PERSPECTIVES There is an increasing awareness that our approach to treating age-related diseases needs to be fundamentally guided by clear knowledge of the underlying mechanisms linking aging and these disease processes rather than purely focusing on disease-specific symptoms and phenotypes. This will undoubtedly provide new avenues for prevention, early intervention, and treatment. Furthermore, the reversibility of epigenetic changes that occur as a hallmark of aging offers exciting opportunities for treating age-related diseases like cancer. An important goal for the future, however, will be to identify disease-modifying drugs that can reverse the overlapping aberrant epigenetic changes that occur as a shared hallmark of aging and cancer. Although several specific compounds that target epigenetic enzymes have been developed and have met with some clinical success, a key challenge in this approach will be to overcome the therapeutic resistance that often accompanies prolonged treatment with these agents. The use of combinatorial treatment modalities offers a promising solution, and the development of approaches and technologies in which epigenetic changes can be used as accurate signatures for guiding these treatments will become imperative in the future. In this respect, continued efforts are needed in the search for epigenetic biomarkers in both aging and age-associated diseases through avenues like parallel genome-wide ultrahigh-throughput sequencing. The discovery of such epigenetic biomarkers can then be exploited to test what aspect of these epigenomic signatures can be utilized for disease prevention and therapy both alone and in combination with existing drugs to achieve optimum efficacy.

Acknowledgments This publication is made possible, in part, with support from the Indiana Clinical and Translational Sciences Institute (CTSI) funded from the NationalInstitutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award (to TL), V foundation Kay Yow Cancer Fund (Grant 4486242 to TL), NIH-NIGMS Grant (#1R01GM120156-01A1 (to TL), and100 VOH Grant (#2987613 to TL), as well as NIH-NCI Grant (#1R03CA223906-01).

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