Emerging Roles of Mammalian Sirtuin SIRT7 in Cancer
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Published OnlineFirst February 17, 2014; DOI: 10.1158/1078-0432.CCR-13-1547 Clinical Cancer Molecular Pathways Research Molecular Pathways: Emerging Roles of Mammalian Sirtuin SIRT7 in Cancer Silvana Paredes1,2, Lidia Villanova1,2,3, and Katrin F. Chua1,2 Abstract SIRT7 belongs to the Sirtuin family of NAD-dependent enzymes, the members of which play diverse roles in aging, metabolism,and disease biology.Increased SIRT7expression isobserved inhumancancers and growing evidence suggests important SIRT7 functions in fundamental cellular programs with an impact on oncogenic transformation and tumor biology. SIRT7 associates with chromatin, where it catalyzes selective deacetylation of lysine 18 on histone H3 (H3K18), an emerging epigenetic biomarker of aggressive tumors and poor clinical outcome in patients with cancer. Through H3K18 deacetylation at specific promoters, SIRT7 controls a tumor-suppressive gene expression program that stabilizes the transformed state of cancer cells. SIRT7 also orchestrates several molecular processes, including rRNA and tRNA synthesis, which ultimately promote the increased ribosome biogenesis necessary for tumor cell growth and proliferation. Remarkably, inactivation of SIRT7 can reverse the transformed phenotype of cancer cells and reduce their tumorigenicity in vivo. These findings place SIRT7 at the crossroads of chromatin signaling, metabolic, and tumor-regulatory pathways. Thus, SIRT7 is a promising pharmacologic target for epigenetic cancer therapy. The development of SIRT7 modulators may allow new therapeutic strategies that control tumor progression by reprogramming the chromatinlandscapeandbiosyntheticmachineryofcancercells.ClinCancerRes;20(7);1741–6.Ó2014AACR. Background particularly cancer. First, SIRT7 is a lysine deacetylase that The founding member of the Sirtuin family of enzymes, selectively removes a specific histone mark, acetylated Saccharomyces cerevisiae Sir2p, is a chromatin silencing fac- H3K18 (H3K18Ac), depletion of which is associated with tor that prevents genomic instability and cellular senescence highly malignant cancers and poor patient prognosis (7). In by catalyzing the lysine deacetylation of histones (1, 2). addition, SIRT7 is enriched in nucleoli (8), subnuclear sites Although some Sirtuins have evolved alternative enzymatic of ribosome assembly that are increased in size and number activities (3, 4), much work has centered on Sirtuins as class in aggressive tumors (9). SIRT7 has an impact on ribosome III deacetylase enzymes (5). Sirtuins differ from class I and biogenesis through multiple mechanisms, and may thereby class II deacetylases in their catalytic mechanisms and play a major role in supporting the high biosynthetic pharmacologic sensitivities, and are uniquely dependent on and metabolic demands of cancer cells. Through these and þ NAD , a molecule whose levels are intimately linked to other functions, SIRT7 is a central coordinator of epigenetic cellular metabolism (1, 5). Not surprisingly, sirtuins are and cellular homeostatic programs that support cancer major players in molecular responses to metabolic stress progression. and cellular homeostasis changes. The seven mammalian Sirtuins, SIRT1–SIRT7, have dis- Reprogramming tumor-suppressive gene expression tinct biologic functions, enzymatic activities, substrates, by selective H3K18 deacetylation and expression patterns (6). SIRT7 is possibly the least Cancer cells exhibit epigenetic chromatin alterations understood mammalian sirtuin, but it has several features in global levels of histone marks and at specific gene that suggest that its activity is important for human disease, regulatory sequences. A study of the genome-wide patterns of 39 histone modifications found that H3K18Ac is one of 17 modifications that form a "back-bone module" that is found at 25% of human promoters and correlate with Authors' Affiliations: 1Department of Medicine, Division of Endocrinology, Gerontology, and Metabolism, School of Medicine, Stanford University, intermediate levels of gene expression (10). These modifi- Stanford; 2Geriatric Research, Education, and Clinical Center, VA Palo Alto cations are proposed to function cooperatively to prepare Health Care System, Palo Alto, California; and 3Department of Experimen- tal Medicine, Sapienza University, Rome, Italy chromatin for transcriptional activation. However, despite this apparent coregulation of many histone marks, clinico- Corresponding Author: Katrin F. Chua, Stanford University School of Medicine, 300 Pasteur Drive, Grant Building S-025, Stanford, CA 94305- pathologic studies indicate that in multiple tumor tissues, 5103. Phone: 650-796-1256; Fax: 650-725-7085; depletion of H3K18Ac in particular is strongly correlated E-mail: [email protected] with cancer disease severity. Indeed, in diverse adenocarci- doi: 10.1158/1078-0432.CCR-13-1547 nomas (including prostate, lung, and kidney tumors), glob- Ó2014 American Association for Cancer Research. al hypoacetylation of H3K18 was prognostic of aggressive www.aacrjournals.org 1741 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2014 American Association for Cancer Research. Published OnlineFirst February 17, 2014; DOI: 10.1158/1078-0432.CCR-13-1547 Paredes et al. cancer phenotypes and poor patient survival (11–13). Finally, SIRT7 is reported to inhibit signaling by the tumor DecreasedglobalH3K18Aclevelsarealsolinkedtoepigenetic suppressor p53 in mouse cardiomyocytes (Fig. 1C), reprogramming during oncogenic transformation by viral although there is conflicting data on whether SIRT7 directly oncoproteins such as adenoviral E1A (14, 15). Thus, deacetylates p53 (7, 8, 27). H3K18 hypoacetylation is a potential biomarker for advanced In summary, much evidence indicates that SIRT7 plays an disease in human cancer and changes in the genome-wide important role in the maintenance of epigenetic patterns of distribution of H3K18Ac are proposed to control epigenetic H3K18 acetylation in cancer cells, which in turn drive gene gene expression programs that drive cancer progression expression programs that stabilize the transformed pheno- (14, 15). types of these cells. Future work should uncover additional While many lysine deacetylases are relatively promiscu- pathways through which SIRT7 influences cancer cell epi- ous, SIRT7 stands out in having high selectivity for deace- genetics through histone deacetylation at chromatin or tylating H3K18Ac. SIRT7 is the only known H3K18Ac- novel mechanisms. specific deacetylase enzyme and plays an essential role in establishing the genome-wide landscape of H3K18Ac (7). Nucleolar guardian of ribosome biogenesis and SIRT7 deacetylates H3K18Ac at promoters of a network of protein homeostasis genes with multiple links to tumor suppression (7). It is Nucleoli are factories where ribosomal RNA (rRNA) is directed to a subset of these genes by interacting with the expressed and assembled with ribosomal proteins into ELK4 transcription factor, which is implicated in prostate ribosomal complexes. Metabolically active tumor cells and other cancers (16–18). When SIRT7 was inactivated in show dramatically increased nucleolar size and number, fibrosarcoma, osteosarcoma, or prostate carcinoma cell which support the increased protein synthesis requirements lines, H3K18 hyperacetylation led to upregulation of the of these cells (9). Indeed, enhanced rRNA synthesis is now tumor-suppressive gene network and reversal of important proposed to be an essential hallmark of cancer cells (28). hallmarks of oncogenic transformation, including anchor- Early studies showed that SIRT7 is enriched in nucleoli, age independent growth, loss of contact inhibition, and where it associates with POLI and rDNA sequences (Fig. 1B; growth factor–independent proliferation. Most strikingly, refs. 8, 29). This finding was intriguing, because yeast Sir2p depletion of SIRT7 dramatically reduced (by more than also localizes to rDNA in nucleoli, and one of its central 75%) the tumorigenicity of multiple cancer cell types (e.g., functions is to suppress rDNA transcription by histone U251 glioblastoma and Hep3B hepatocellular carcinoma deacetylation (1). It is surprising, however, that SIRT7 was cells) in mouse xenograft assays in vivo (7, 19). Thus, SIRT7 found to activate, not repress, rDNA transcription (29). plays a fundamental role in epigenetic maintenance of the Moreover, reduced rRNA synthesis in SIRT7-depleted cancer neoplastic state of cancer cells. cells was associated with decreased cell viability and pro- Another major category of SIRT7 target genes consists of liferation (29). This observation suggested that increased ribosomal protein genes, which are transcriptional targets SIRT7 activity in cancer cells might fuel tumor growth by of the oncoprotein MYC (Fig. 1A; refs. 7, 20). By opposing promoting rRNA synthesis and ribosome biogenesis. MYC-dependent expression of ribosomal proteins, SIRT7 The effect of SIRT7 on rRNA synthesis depends on an plays an adaptive role in the Unfolded Protein Response intact SIRT7 catalytic domain, but the molecular substrate (UPR) to suppress endoplasmic reticulum (ER) stress (20). of SIRT7 in this context was not initially clear. Indeed, In the liver, chronic ER stress in SIRT7-deficient mice leads histone deacetylation by SIRT7 would have the opposite to fatty liver disease. In cancer cells, SIRT7 prevents ER effect on rDNA transcription. Recent findings now reveal stress–induced apoptosis in a MYC-dependent manner that SIRT7 can control transcription of rDNA through (20).