Epigenetics of cancer and aging

The 14th theory of aging described in my treatise is Programmed Epigenomic Changes.  But exactly what are the epigenomic changes and how do they work?  Much is still to be learned in this area but recent research is going a long way to increase our understanding.  A great deal of this research has focused on epigenetic mechanisms in certain cancers but many of the lessons being learned also relate to aging  This blog entry reviews selected research publications on topics related to the epigenetics of certain cancers and aging. 

The two most- studied forms of epigenetic changes are:

·        DNA methylation of the promoter regions of certain genes, generally resulting in the silencing of the affected genes. If a pro-apoptic gene like P53 is silenced, for example, the result can be tumor formation.  If a longevity-related gene like SIRT1 is silenced, the result could be susceptibility to an age-related disease like diabetes and shortened lifespan.  Or, silencing SIRT1 in a cancer cell might lead that cell to die.  If certain DNA repair genes like WRN are methylated and silenced, the result can be premature aging. “DNA methylation also affects the expression of genes involved in maintaining the integrity of the genome through DNA repair and detoxification of reactive oxygen species(ref).”  Of particular interest from the viewpoint of DNA methylation in mammals are the so-called CpG islands.  “CpG islands typically occur at or near the transcription start site of genes, particularly housekeeping genes, in vertebrates.[2]  – “Unlike CpG sites in the coding region of a gene, in most instances, the CpG sites in the CpG islands of promoters are unmethylated if genes are expressed(ref).”

·        Histone deacetylation and acetylation, generally having to do respectively with silencing or unsilencing of genes.   Histones are spindles in a cell’s nucleus around which DNA is wrapped; they play important roles in gene activation.  Histone acetylation is a chemical modification of a portion of a histone which leads to selective unwrapping of the DNA making the exposed genes amenable to activation and expression.  Histone deacetylation is the opposite.  

For further background on what is covered here you can review some of my previous blog posts including Epigenetics, epigenomics and aging, DNA methylation, personalized medicine and longevity, Histone acetylase and deacetylase inhibitors, Homicide by DNA methylation, Epigenomic complexity, Epigenetics going mainstream, DNA repair cleanup failure – a root cause for cancers?   and Genomic stability, DNA repair and the sirtuin SIRT6. The May 2010 blog entry Epigenetics, inflammation, cancer, immune system, neurological and cardiovascular disease and aging quotes from publications dealing with practical applications of epigenetics in a variety of biological situations.  This current blog post focuses on cancers and aging.


The 2010 publication DNA methylation and cancer provides an overview on DNA methylation.  “DNA methylation is one of the most intensely studied epigenetic modifications in mammals. In normal cells, it assures the proper regulation of gene expression and stable gene silencing. DNA methylation is associated with histone modifications and the interplay of these epigenetic modifications is crucial to regulate the functioning of the genome by changing chromatin architecture. The covalent addition of a methyl group occurs generally in cytosine within CpG dinucleotides which are concentrated in large clusters called CpG islands. DNA methyltransferases are responsible for establishing and maintenance of methylation pattern. It is commonly known that inactivation of certain tumor-suppressor genes occurs as a consequence of hypermethylation within the promoter regions and a numerous studies have demonstrated a broad range of genes silenced by DNA methylation in different cancer types. On the other hand, global hypomethylation, inducing genomic instability, also contributes to cell transformation. Apart from DNA methylation alterations in promoter regions and repetitive DNA sequences, this phenomenon is associated also with regulation of expression of noncoding RNAs such as microRNAs that may play role in tumor suppression. DNA methylation seems to be promising in putative translational use in patients and hypermethylated promoters may serve as biomarkers. Moreover, unlike genetic alterations, DNA methylation is reversible what makes it extremely interesting for therapy approaches. The importance of DNA methylation alterations in tumorigenesis encourages us to decode the human epigenome. Different DNA methylome mapping techniques are indispensable to realize this project in the future.” 

Research findings

Typical patterns of GPC island methylation together with certain mutations appear to be associated with specific cancers

Colorectal cancer is one of the most-studied in this regard.  Going back to 2007, the publication TGFBR2 mutation is correlated with CpG island methylator phenotype in microsatellite instability-high colorectal cancer reports “The transforming growth factor-beta receptor type 2 gene (TGFBR2) is mutated in most microsatellite instability-high (MSI-H) colorectal cancers. Promoter methylation of RUNX3 (runt-related transcription factor 3; encoding a transcription factor downstream of the TGF-beta pathway) is observed in colorectal cancer with CpG island methylator phenotype (CIMP), which is characterized by extensive promoter methylation and is associated with MSI-H and BRAF mutations. —  Using 144 MSI-H colorectal cancers derived from 2 large prospective cohort studies, we analyzed a mononucleotide repeat of TGFBR2 and quantified DNA methylation (by MethyLight technology) in 8 CIMP-specific promoters  –.  After stratification by sex, location, tumor differentiation, RUNX3 status, KRAS/BRAF status, or p53 status, CIMP-high was persistently correlated with TGFBR2 mutation. In contrast, RUNX3, KRAS, or BRAF status was no longer correlated with TGFBR2 mutation after stratification by CIMP status. In conclusion, TGFBR2 mutation is associated with CIMP-high and indirectly with RUNX3 methylation. Our findings emphasize the importance of analyzing global epigenomic status (for which CIMP status is a surrogate marker) when correlating a single epigenetic event (eg, RUNX3 methylation) with any other molecular or clinicopathologic variables.” 

[“Microsatellites are repeated sequences of DNA. Although the length of these microsatellites is highly variable from person to person, each individual has microsatellites of a set length. — These repeated sequences are common, and normal. — The appearance of abnormally long or short microsatellites in an individual’s DNA is referred to as microsatellite instability. Microsatellite instability (MSI) is a condition manifested by damaged DNA due to defects in the normal DNA repair process.[1] Sections of DNA called microsatellites, which consist of a sequence of repeating units of 1-6 base pairs in length, become unstable and can shorten or lengthen, –(ref)”]

The 2008 publication Comprehensive biostatistical analysis of CpG island methylator phenotype in colorectal cancer using a large population-based sample reports “The CpG island methylator phenotype (CIMP) is a distinct phenotype associated with microsatellite instability (MSI) and BRAF mutation in colon cancer.DNA methylation at 16 CpG islands [CACNA1G, IGF2, NEUROG1, RUNX3 and SOCS1 plus CDKN2A (p16), CHFR, CRABP1, HIC1, IGFBP3, MGMT, MINT1, MINT31, MLH1, p14 (CDKN2A/ARF) and WRN] was quantified in 904 colorectal cancers by real-time PCR (MethyLight).multivariate logistic regression demonstrated that CIMP-high was independently associated with older age, proximal location, poor differentiation, MSI-high, BRAF mutation, and inversely with LINE-1 hypomethylation and beta-catenin (CTNNB1) activation. — CONCLUSIONS: Our study provides valuable data for standardization of the use of CIMP-high-specific methylation markers. CIMP-high is independently associated with clinical and key molecular features in colorectal cancer. Our data also suggest that KRAS mutation is related with a random CpG island methylation pattern which may lead to CIMP-low tumors.”

The 2010 review publication DNA methylation markers in colorectal cancer reports: “Colorectal cancer (CRC) arises as a consequence of the accumulation of genetic and epigenetic alterations in colonic epithelial cells during neoplastic transformation. Epigenetic modifications, particularly DNA methylation in selected gene promoters, are recognized as common molecular alterations in human tumors. Substantial efforts have been made to determine the cause and role of aberrant DNA methylation (“epigenomic instability”) in colon carcinogenesis. In the colon, aberrant DNA methylation arises in tumor-adjacent, normal-appearing mucosa. Aberrant methylation also contributes to later stages of colon carcinogenesis through simultaneous methylation in key specific genes that alter specific oncogenic pathways. Hypermethylation of several gene clusters has been termed CpG island methylator phenotype and appears to define a subgroup of colon cancer distinctly characterized by pathological, clinical, and molecular features. DNA methylation of multiple promoters may serve as a biomarker for early detection in stool and blood DNA and as a tool for monitoring patients with CRC. DNA methylation patterns may also be predictors of metastatic or aggressive CRC. Therefore, the aim of this review is to understand DNA methylation as a driving force in colorectal neoplasia and its emerging value as a molecular marker in the clinic.”

The 2010 publication [Promoter hypermethylation and CpG island methylator phenotype in colorectal carcinogenesis] summarizes the situation.  “Amino acid alterations or insufficient protein synthesis caused by the mutation on genes has long been recognized as the main mechanism of silencing of suppressor genes leading to carcinogenesis. However, epigenetic silencing of the cancer related genes induced by hyper-methylation of promoter is recognized as an additional important molecular mechanism for carcinogenesis. Differing molecular mechanisms of colorectal carcinogenesis have become known after advanced understanding of genes silenced by promoter methylation.” 

Hypomethylation as well as hypermethylation can play roles in cancer susceptibility and ill-health

Some genes can best remain methylated.  The 2010 publication Epigenomic diversity of colorectal cancer indicated by LINE-1 methylation in a database of 869 tumors reports “BACKGROUND: Genome-wide DNA hypomethylation plays a role in genomic instability and carcinogenesis. LINE-1 (L1 retrotransposon) constitutes a substantial portion of the human genome, and LINE-1 methylation correlates with global DNA methylation status. LINE-1 hypomethylation in colon cancer has been strongly associated with poor prognosis. However, whether LINE-1 hypomethylators constitute a distinct cancer subtype remains uncertain. Recent evidence for concordant LINE-1 hypomethylation within synchronous colorectal cancer pairs suggests the presence of a non-stochastic mechanism influencing tumor LINE-1 methylation level. Thus, it is of particular interest to examine whether its wide variation can be attributed to clinical, pathologic or molecular features. — DESIGN: Utilizing a database of 869 colorectal cancers in two prospective cohort studies, we constructed multivariate linear and logistic regression models for LINE-1 methylation (quantified by Pyrosequencing). Variables included age, sex, body mass index, family history of colorectal cancer, smoking status, tumor location, stage, grade, mucinous component, signet ring cells, tumor infiltrating lymphocytes, CpG island methylator phenotype (CIMP), microsatellite instability, expression of TP53 (p53), CDKN1A (p21), CTNNB1 (beta-catenin), PTGS2 (cyclooxygenase-2), and FASN, and mutations in KRAS, BRAF, and PIK3CA. — CONCLUSIONS: LINE-1 extreme hypomethylators appear to constitute a previously-unrecognized, distinct subtype of colorectal cancers, which needs to be confirmed by additional studies. Our tumor LINE-1 methylation data indicate enormous epigenomic diversity of individual colorectal cancers.”

Hypermethylation of microRNA genes can play roles in cancers

The 2008 publication Inactivation of miR-34a by aberrant CpG methylation in multiple types of cancer reports “Recently, we and others identified the microRNA miR-34a as a target of the tumor suppressor gene product p53. Ectopic miR-34a induces a G(1) cell cycle arrest, senescence and apoptosis. Here we report that miR-34a expression is silenced in several types of cancer due to aberrant CpG methylation of its promoter. 19 out of 24 (79.1%) primary prostate carcinomas displayed CpG methylation of the miR-34a promoter and concomitant loss of miR-34a expression. CpG methylation of the miR-34a promoter was also detected in breast (6/24; 25%), lung (7/24; 29.1%), colon (3/23; 13%), kidney (3/14; 21.4%), bladder (2/6; 33.3%) and pancreatic (3/19; 15.7%) carcinoma cell lines, as well as in melanoma cell lines (19/44; 43.2%) and primary melanoma (20/32 samples; 62.5%). Silencing of miR-34a was dominant over its transactivation by p53 after DNA damage. Re-expression of miR-34a in prostate and pancreas carcinoma cell lines induced senescence and cell cycle arrest at least in part by targeting CDK6. These results show that miR-34a represents a tumor suppressor gene which is inactivated by CpG methylation and subsequent transcriptional silencing in a broad range of tumors. 

The 2010 publication Epigenetic silencing of miR-137 is an early event in colorectal carcinogenesis reports “Global downregulation of microRNAs (miRNA) is a common feature in colorectal cancer (CRC). Whereas CpG island hypermethylation constitutes a mechanism for miRNA silencing, this field largely remains unexplored. Herein, we describe the epigenetic regulation of miR-137 and its contribution to colorectal carcinogenesis. We determined the methylation status of miR-137 CpG island in a panel of six CRC cell lines and 409 colorectal tissues [21 normal colonic mucosa from healthy individuals (N-N), 160 primary CRC tissues and their corresponding normal mucosa (N-C), and 68 adenomas]. TaqMan reverse transcription-PCR and in situ hybridization were used to analyze miR-137 expression. In vitro functional analysis of miR-137 was performed. Gene targets of miR-137 were identified using a combination of bioinformatic and transcriptomic approaches. We experimentally validated the miRNA:mRNA interactions. Methylation of the miR-137 CpG island was a cancer-specific event and was frequently observed in CRC cell lines (100%), adenomas (82.3%), and CRC (81.4%), but not in N-C (14.4%; P < 0.0001 for CRC) and N-N (4.7%; P < 0.0001 for CRC). Expression of miR-137 was restricted to the colonocytes in normal mucosa and inversely correlated with the level of methylation. Transfection of miR-137 precursor in CRC cells significantly inhibited cell proliferation. Gene expression profiling after miR-137 transfection discovered novel potential mRNA targets. We validated the interaction between miR-137 and LSD-1. Our data indicate that miR-137 acts as a tumor suppressor in the colon and is frequently silenced by promoter hypermethylation. Methylation silencing of miR-137 in colorectal adenomas suggests it to be an early event, which has prognostic and therapeutic implications.” 

Aberrant DNA methylation and histone modifications can work together to induce silencing of miRNA genes in cancers 

The 2009 publication Epigenetic regulation of microRNA expression in colorectal cancer reports “In the last years, microRNAs (miRNA) have emerged as new molecular players involved in carcinogenesis. Deregulation of miRNAs expression has been shown in different human cancer but the molecular mechanism underlying the alteration of miRNA expression is unknown. To identify tumor-supressor miRNAs silenced through aberrant epigenetic events in colorectal cancer (CRC), we used a sequential approach. We first identified 5 miRNAs down-regulated in patient with colorectal cancer samples and located around/on a CpG island. Treatment with a DNA methyltransferase inhibitor and a HDAC inhibitor restored expression of 3 of the 5 microRNAs (hsa-miR-9, hsa-miR-129 and hsa-miR-137) in 3 CRC cell lines. Expression of hsa-miR-9 was inversely correlated with methylation of their promoter regions as measure by MSP and bisulphate sequencing. Further, methylation of the hsa-miR-9-1, hsa-miR-129-2 and hsa-miR-137 CpG islands were frequently observed in CRC cell lines and in primary CRC tumors, but not in normal colonic mucosa. Finally, methylation of hsa-miR-9-1 was associated with the presence of lymph node metastasis. In summary, our results aid in the understanding of miRNA gene regulation showing that aberrant DNA methylation and histone modifications work together to induce silencing of miRNAs in CRC.” 

P53 apoptotic protection in cancers can be subverted by promoter methylation and silencing of its microRNA components microRNA-34b/c

The 2008 publication Epigenetic silencing of microRNA-34b/c and B-cell translocation gene 4 is associated with CpG island methylation in colorectal cancer relates “Altered expression of microRNA (miRNA) is strongly implicated in cancer, and recent studies have shown that, in cancer, expression of some miRNAs cells is silenced in association with CpG island hypermethylation. To identify epigenetically silenced miRNAs in colorectal cancer (CRC), we screened for miRNAs induced in CRC cells by 5-aza-2′-deoxycytidine (DAC) treatment or DNA methyltransferase knockout. We found that miRNA-34b (miR-34b) and miR-34c, two components of the p53 network, are epigenetically silenced in CRC; that this down-regulation of miR-34b/c is associated with hypermethylation of the neighboring CpG island; and that DAC treatment rapidly restores miR-34b/c expression. Methylation of the miR-34b/c CpG island was frequently observed in CRC cell lines (nine of nine, 100%) and in primary CRC tumors (101 of 111, 90%), but not in normal colonic mucosa. Transfection of precursor miR-34b or miR-34c into CRC cells induced dramatic changes in the gene expression profile, and there was significant overlap between the genes down-regulated by miR-34b/c and those down-regulated by DAC. We also found that the miR-34b/c CpG island is a bidirectional promoter which drives expression of both miR-34b/c and B-cell translocation gene 4 (BTG4); that methylation of the CpG island is also associated with transcriptional silencing of BTG4; and that ectopic expression of BTG4 suppresses colony formation by CRC cells. Our results suggest that miR-34b/c and BTG4 are novel tumor suppressors in CRC and that the miR-34b/c CpG island, which bidirectionally regulates miR-34b/c and BTG4, is a frequent target of epigenetic silencing in CRC.”

This document also points out how a hypermethylation problem in the miR-34b/c CpG island can be cleared up using a demethylation agent DAC.  This agent, 5-Aza-2′-deoxycytidine, has been known for some time to inhibit promoter methylation and to suppress the growth of certain tumor cell lines. “We exposed seven human tumor cell lines and two human fibroblast cell strains to the demethylating agent, 5-aza-2′-deoxycytidine (5-Aza-CdR), to determine whether the silencing of growth-regulatory genes by de novo methylation in immortalized cell lines could be reversed, possibly restoring growth control. After recovery from the immediate cytotoxic effects of 5-Aza-CdR, this agent suppressed cellular growth in all seven tumor lines but not in either fibroblast strain(ref).”

The 2010 publication The miR-34 family in cancer and apoptosis is a review paper confirming the role of hypermethylation in miR-34a/b/c as inactivating P53 protection in a variety of tumor types including neuroblastomas: “Recently, the transcription factor encoded by tumor suppressor gene p53 was shown to regulate the expression of microRNAs. The most significant induction by p53 was observed for the microRNAs miR-34a and miR-34b/c, which turned out to be direct p53 target genes. Ectopic miR-34 expression induces apoptosis, cell-cycle arrest or senescence. In many tumor types the promoters of the miR-34a and the miR-34b/c genes are subject to inactivation by CpG methylation. MiR-34a resides on 1p36 and is commonly deleted in neuroblastomas. Furthermore, the loss of miR-34 expression has been linked to resistance against apoptosis induced by p53 activating agents used in chemotherapy. In this review, the evidence for a role of miR-34a and miR-34b/c in the apoptotic response of normal and tumor cells is surveyed.”  This knowledge could conceivably lead to treatments for otherwise untreatable and rapid-killer diseases like gliablastoma. 

Additional interesting publications relating CpG Island methylator phenotype (CIMP) to cancers are (2010) NGX6 gene mediated by promoter methylation as a potential molecular marker in colorectal cancer,  (2009) Colon tumor mutations and epigenetic changes associated with genetic polymorphism: insight into disease pathways and the 2006 report Association of smoking, CpG island methylator phenotype, and V600E BRAF mutations in colon cancer. 

Histone deacetylase inhibition is being investigated as an epigenetic treatment for cancers

For example, the 2009 publication Epigenetic Targeting of Transforming Growth Factor beta Receptor II and Implications for Cancer Therapy reports “The transforming growth factor (TGF) beta signaling pathway is involved in many cellular processes including proliferation, differentiation, adhesion, motility and apoptosis. The loss of TGFbeta signaling occurs early in carcinogenesis and its loss contributes to tumor progression. The loss of TGFbeta responsiveness frequently occurs at the level of the TGFbeta type II receptor (TGFbetaRII) which has been identified as a tumor suppressor gene (TSG). In keeping with its TSG role, the loss of TGFbetaRII expression is frequently associated with high tumor grade and poor patient prognosis.   Reintroduction of TGFbetaRII into tumor cell lines results in growth suppression. Mutational loss of TGFbetaRII has been characterized, particularly in a subset of colon cancers with DNA repair enzyme defects. However, the most frequent cause of TGFbetaRII silencing is through epigenetic mechanisms. Therefore, re-expression of TGFbetaRII by use of epigenetic therapies represents a potential therapeutic approach to utilizing the growth suppressive effects of the TGFbeta signaling pathway. However, the restoration of TGFbeta signaling in cancer treatment is challenging because in late stage disease, TGFbeta is a pro-metastatic factor. This effect is associated with increased expression of the TGFbeta ligand. In this Review, we discuss the mechanisms associated with TGFbetaRII silencing in cancer and the potential usefulness of histone deacetylase (HDAC) inhibitors in reversing this effect. The use of HDAC inhibitors may provide a unique opportunity to restore TGFbetaRII expression in tumors as their pleiotropic effects antagonize many of the cellular processes, which mediate the pro-metastatic effects associated with increased TGFbeta expression.” 

The SIRT1 gene is activated in cancers – whoops!

In the course of this discussion we find that another familiar gene SIRT1 is involved in a whole new context.  In previous blog entries and in the aging-science community, SIRT1 has been mainly discussed as a longevity gene, the one involved in calorie restriction.  And activation of SIRT1 via substances such as resveratrol has been seen as a very good thing for longevity(ref)(ref)(ref).  However, the flip side is that the SIRT1 gene is activated in many cancers and it has been suggested that SIRT1 inhibition may provide an approach to shrinking tumors.

The 2009 publication SIRT1 histone deacetylase expression is associated with microsatellite instability and CpG island methylator phenotype in colorectal cancer speaks to this issue.  “The class III histone deacetylase SIRT1 (sir2) is important in epigenetic gene silencing. Inhibition of SIRT1 reactivates silenced genes, suggesting a possible therapeutic approach of targeted reversal of aberrantly silenced genes. In addition, SIRT1 may be involved in the well-known link between obesity, cellular energy balance and cancer. However, a comprehensive study of SIRT1 using human cancer tissue with clinical outcome data is currently lacking, and its prognostic significance is uncertain. Using the database of 485 colorectal cancers in two independent prospective cohort studies, we detected SIRT1 overexpression in 180 (37%) tumors by immunohistochemistry. We examined its relationship to the CpG island methylator phenotype (CIMP), related molecular events, clinical features including body mass index, and patient survival. We quantified DNA methylation in eight CIMP-specific promoters (CACNA1G, CDKN2A, CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1) and eight other CpG islands (CHFR, HIC1, IGFBP3, MGMT, MINT1, MINT31, p14, and WRN) by MethyLight. SIRT1 overexpression was associated with CIMP-high (> or =6 of 8 methylated CIMP-specific promoters, P=0.002) and microsatellite instability (MSI)-high phenotype (P<0.0001).  — In both univariate and multivariate analyses, SIRT1 overexpression was significantly associated with the CIMP-high MSI-high phenotype (multivariate odds ratio, 3.20; 95% confidence interval, 1.35-7.59; P=0.008). In addition, mucinous component (P=0.01), high tumor grade (P=0.02), and fatty acid synthase overexpression (P=0.04) were significantly associated with SIRT positivity in multivariate analysis. SIRT1 was not significantly related with age, sex, tumor location, stage, signet ring cells, cyclooxygenase-2 (COX-2), LINE-1 hypomethylation, KRAS, BRAF, BMI, PIK3CA, HDAC, p53, beta-catenin, COX-2, or patient prognosis. In conclusion, SIRT1 expression is associated with CIMP-high MSI-high colon cancer, suggesting involvement of SIRT1 in gene silencing in this unique tumor subtype.”

P53 in the absence of hypomethylation activates the microRNA miR-34a resulting in reduced SIRT1 and tumor suppression, at least in glioma cells    

Going further, the 2010 publication MicroRNA-34a: a novel tumor suppressor in p53-mutant glioma cell line U25 relates “BACKGROUND AND AIMS: Previous studies showed that microRNA-34 (miR-34a) family was found to be a direct target of p53, functioning downstream of the p53 pathway as tumor suppressors. MiR-34a was identified to represent the status of p53 and participate in initiation and progress of cancers. We undertook this study to investigate the role of miR-34a in glioma cells. — METHODS: Expression levels of miR-34a in glioma cell lines and normal brains were detected using qRT-PCR. Human U251 glioma cells were transfected with miR-34a mimics, and the effects of miR-34a restoration were assessed by MTT assays, cell cycle analysis, caspase-3 activation, and in vitro migration and invasion assays. A computational search revealed a conserved target site of miR-34a within the 3′-untranslated region of SIRT1. Luciferase reporter assay was performed to examine the effects of miR-34a on expression of potential target gene SIRT1, and mRNA and protein expression of SIRT1 after miR-34a transfection were detected by qRT-PCR and Western blot analysis. — RESULTS: MiR-34a expression was markedly reduced in p53-mutant cells U251 compared with A172 and SHG-44 cells expressing wild-type p53 and normal brains. Overexpression of miR-34a in U251 cells resulted in inhibition of cell growth and arrest in G0-G1 phase and induced apoptosis. Also, restoration of miR-34a significantly reduced in vitro migration and invasion capabilities. Reporter assays indicated that SIRT1 was a direct target of miR-34a. In U251 cells, overexpression of miR-34a decreased SIRT1 protein levels but not mRNA expressions, which demonstrated miR-34a-induced SIRT1 inhibition occurred at the posttranscriptional level. — CONCLUSIONS: Our results demonstrate that miR-34a acts as a tumor suppressor in p53-mutant glioma cells U251, partially through regulating SIRT1.”

There has been controversy about the positive or negative roles SIRT1 plays in cancers.  The probable bottom line is that SIRT1 and SIRT1 activators including resveratrol can play positive roles in both preventing/treating cancers and extending lifespans

To delve further into the role of SIRT1 in cancers and aging and its relationship to epigenetics I quote rather extensively from the 2009 publication SIRT1, Is It a Tumor Promoter or Tumor Suppressor?SIRT1 has been considered as a tumor promoter because of its increased expression in some types of cancers and its role in inactivating proteins that are involved in tumor suppression and DNA damage repair. However, recent studies demonstrated that SIRT1 levels are reduced in some other types of cancers, and that SIRT1 deficiency results in genetic instability and tumorigenesis, while overexpression of SIRT1 attenuates cancer formation in mice heterozygous for tumor suppressor p53 or APC. Here, I review these recent findings and discuss the possibility that activation of SIRT1 both extends lifespan and inhibits cancer formation. — SIRT1, a proto member of the sirtuin family, modifies histones through deacetylation of K26 in histone H1 (H1K26), K9 in histone H3 (H3K9) and K16 in histone H4 (H4K16). It also deacetylates many non-histone proteins that are involved in cell growth, apoptosis, neuronal protection, adaptation to calorie restriction, organ metabolism and function, cell senescence, and tumorigenesis [1, 35]. However, it remains controversial whether SIRT1 acts as a tumor promoter or tumor suppressor due to recent controversy over SIRT1 regarding: 1) its expression level in human cancers; 2) its activity on tumor suppressors and oncoproteins; 3) its effect on growth arrest, cell death, and DNA damage repair; and, finally, 4) its long-term impact on lifespan and cancer risk.”

Going on “It has been shown that SIRT1 is significantly elevated in human prostate cancer [6], acute myeloid leukemia [7], and primary colon cancer [8]. Hida et al. examined SIRT1 protein levels in several different types of skin cancer by immunohistochemical analysis [9]. Overexpression of SIRT1 was frequently observed in all kinds of non-melanoma skin cancers including squamous cell carcinoma, basal cell carcinoma, Bowen’s disease, and actinic keratosis. Based on the elevated levels of SIRT1 in cancers, it was hypothesized that SIRT1 serves as a tumor promoter [10]. However it does not rule out a possibility that increased expression of SIRT1 is a consequence, rather than a cause, of tumorigenesis. In contrast, Wang et al. analyzed a public database and found that SIRT1 expression was reduced in many other types of cancers, including glioblastoma, bladder carcinoma, prostate carcinoma and ovarian cancers as compared to the corresponding normal tissues [11]. Their further analysis of 44 breast cancer and 263 hepatic carcinoma cases also revealed reduced expression of SIRT1 in these tumors [11]. These data suggest that SIRT1 acts as a tumor suppressor rather than a promoter in these tissues.”

The author of this paper presents arguments on both sides of the issue.  On the one hand, there are the surface factors that suggest that SIRT1 activation in older people are likely to increase the risk of carcinogenesis, such as high expression of SIRT1 in certain cancers and inhibition of P53 apoptosis of cancer cells by SIRT1.  On the other hand are the factors that suggest that SIRT1 activation is likely to be both protective against cancers and enhance longevity such as feedback loops through which SIRT1 expression indirectly triggers cancer cell death. “To illustrate the molecular mechanism underlying how activated SIRT1 triggers cell death, the researchers demonstrated that SIRT1 negatively regulates expression of Survivin, which encodes an anti-apoptotic protein, by deacetylating H3K9 within the promoter of Survivin [40]. Altogether, these data suggest that SIRT1 mediates BRCA1 signaling and inhibits tumor growth through repressing transcription of oncogenes or activity of oncoproteins.”  Further SIRT1 plays an important rold in DNA damage repair.  “Sirt1-/- cells displayed chromosome aneuploidy and structural aberrations, conceivably originated from the continuous division of abnormal mitosis. SIRT1 deficiency also causes reduced ability to repair DNA-double strand breaks (DSBs), radiation sensitivity, and impaired DDRs characterized by diminished γH2AX, BRCA1, RAD51 and NBS1 foci formation upon γ-irradiation. Thus, SIRT1 may play a role in recruiting these proteins to DNA damage sites. — In response to oxidative DNA damage, SIRT1 dissociates from its original loci and relocalizes to DSBs to promote repair and maintain genome integrity. Their data indicated that the efficient recruitment of SIRT1 to DSBs requires DNA damage signalling through ATM and H2AX. Without SIRT1, recruitment of RAD51 and NBS1 to DSBs was delayed and strongly reduced, thus highlighting a key role of SIRT1 in the DNA damage repair process. The researchers further showed that SIRT1 inhibits a functionally diverse set of genes that are dereprssed by oxidative stress.”

The author come down on the side of SIRT1 playing a highly positive role both for possibly treating cancers and even for possible life extension.  “Aging has been considered as the most potent carcinogen for cancer, as cancer incidence is quickly elevated in the aging population [46]. It is of great interest to define the conditions, in which the activation of SIRT1 can both extend lifespan and inhibits tumor formation. In C. elegans, mutations that increase the lifespan can also inhibit tumor growth [47]. In animal models, caloric restriction, which activates SIRT1, extends lifespan and is also highly protective against cancer [19, 4850]. — Then, can direct activation of SIRT1 both extend lifespan and reduce cancer risk? Several lines of evidence suggest that it is possible. First, it has been shown that activation of SIRT1 by a low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice [51]. Similarly, SRT1720, a more potent and specific agonist in activating SIRT1 than resveratrol [52], mimics low energy levels and protects against diet-induced metabolic disorders by enhancing fat oxidation [49].”

The article concludes “Finally, as illustrated above that SIRT1 overexpression suppresses the age-related transcriptional changes and reduces formation of colon cancer in APC+/min mice [38], BRCA1-associated mammary cancer [40], spontaneous cancers in multiple tissues of Sirt1+/-;p53+/- mice [11], and γ-irradiation induced lymphoma in p53+/- mice [42]. Thus, through improving metabolic conditions by increasing SIRT1 activity, it is possible to both extend lifespan and reduce cancer risk in humans in the foreseeable future.” 

I am inclined to support the author’s optimistic viewpoint.  Like many SIRT1 researchers, I regularly take resveratrol supplements.  I have been doing so for about four years now.

A 2010 publication confirms the central perceptions of the previously-cited one: SIRT1 and p53, effect on cancer, senescence and beyond: “NAD(+)-dependent Class III histone deacetylase SIRT1 is a multiple function protein critically involved in stress responses, cellular metabolism and aging through deacetylating a variety of substrates including p53, forkhead-box transcription factors, PGC-1alpha, NF-kappaB, Ku70 and histones. The first discovered non-histone target of SIRT1, p53, is suggested to play a central role in SIRT1-mediated functions in tumorigenesis and senescence. SIRT1 was originally considered to be a potential tumor promoter since it negatively regulates the tumor suppressor p53 and other tumor suppressors. There is new evidence that SIRT1 acts as a tumor suppressor based on its role in negatively regulating beta-catenin and survivin. This review provides an overview of current knowledge of SIRT1-p53 signaling and controversies regarding the functions of SIRT1 in tumorigenesis.”

There have been a number of additional recent and interesting publications related to SIRT1, its role in longevity pathways, and its molecular activation and inactivation.  I expect to cover these in another blog entry.

About Vince Giuliano

Being a follower, connoisseur, and interpreter of longevity research is my latest career. I have been at this part-time for well over a decade, and in 2007 this became my mainline activity. In earlier reincarnations of my career. I was founding dean of a graduate school and a university professor at the State University of New York, a senior consultant working in a variety of fields at Arthur D. Little, Inc., Chief Scientist and C00 of Mirror Systems, a software company, and an international Internet consultant. I got off the ground with one of the earliest PhD's from Harvard in a field later to become known as computer science. Because there was no academic field of computer science at the time, to get through I had to qualify myself in hard sciences, so my studies focused heavily on quantum physics. In various ways I contributed to the Computer Revolution starting in the 1950s and the Internet Revolution starting in the late 1980s. I am now engaged in doing the same for The Longevity Revolution. I have published something like 200 books and papers as well as over 430 substantive.entries in this blog, and have enjoyed various periods of notoriety. If you do a Google search on Vincent E. Giuliano, most if not all of the entries on the first few pages that come up will be ones relating to me. I have a general writings site at www.vincegiuliano.com and an extensive site of my art at www.giulianoart.com. Please note that I have recently changed my mailbox to vegiuliano@agingsciences.com.
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5 Responses to Epigenetics of cancer and aging

  1. jeg3 says:

    Nice post Vince.

    A while back you asked for website suggestions, it may be nice to have a tab that list all the reference material (and cross-link to post) so when people come across interesting papers they can check to see if you have seen it.

    Have a Happy Holiday Season.

  2. Res says:

    Hi Vince

    Quite a long write up ..
    It would take me long time to complete the reading :))
    un-growth harmone is being investigated for longevity


  3. admin says:


    Thanks for the tip I just am about to put up a new post on HGH and the un-growth inhibitor you mention.


  4. admin says:


    Thanks for the suggestion. I would love to do what you suggest but need to research how to accomplish this as other than a very very long manual task. It would indeed be valuable if I could find a way.


  5. I like the way you write. Organized, concise, yet elaborate. 🙂

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