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The Controversial Role of Sirtuins in Tumorigenesis — SIRT7 Joins The

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The Controversial Role of Sirtuins in Tumorigenesis — SIRT7 Joins The npg 10 Cell Research (2013) 23:10-12. npg © 2013 IBCB, SIBS, CAS All rights reserved 1001-0602/13 $ 32.00 RESEARCH HIGHLIGHT www.nature.com/cr The controversial role of Sirtuins in tumorigenesis – SIRT7 joins the debate Ling Li1, Ravi Bhatia1 1Division of Hematopoietic Stem cell and Leukemia Research, City of Hope National Medical Center, Duarte, CA 91010, USA Cell Research (2013) 23:10-12. doi:10.1038/cr.2012.112; published online 31 July 2012 Sirtuins are NAD-dependent function of SIRT7 is the least well un- first deacetylase with selectivity for the deacetylases that are conserved derstood so far. SIRT7 lacks conserved H3K18Ac modification. Low levels of from yeast to mammals. A new report amino acids within the catalytic domain H3K18Ac were previously shown to sheds light on the function of SIRT7, associated with deacetylase activity, and predict a higher risk of prostate cancer the least understood member of the although suggested to deacetylate the recurrence, and poor prognosis in lung, Sirtuin family by identifying its locus- tumor suppressor p53 (Figure 1) [3], has kidney and pancreatic cancers [8]. Us- specific H3K18 deacetylase activity, generally been considered to have weak ing chromatin immunoprecipitation and linking it to maintenance of cellu- or undetectable deacetylase activity [4, sequencing to study the genome-wide lar transformation in malignancies. 5]. There is evidence that SIRT7 can me- localization of SIRT7, Barber et al. Sirtuins are NAD-dependent deacety- diate protein interactions regulating the found that SIRT7 is enriched at promot- lases that have been linked to longev- RNA Pol I machinery [6]. SIRT7 is most ers for a select set of genes, including ity and genomic stability in yeast prominently expressed in hematopoietic the ribosomal protein genes RPS20, [1]. Sirtuins deacetylate histones and cells, especially myeloid progenitor RPS7, and RPS14, and the tumor sup- non-histone proteins, and are highly cells [4], and is localized on chromo- pressor genes, NME1 and COPS2. conserved from lower organisms to some 17q25.3, a region frequently al- SIRT7 depletion increased H3K18Ac mammals. Seven Sirtuin family mem- tered in acute leukemia and lymphomas at these gene promoters, and increased bers are recognized (SIRT1-7). Sirtuins [4]. In a new report in Nature, Barber transcription of target genes. Although regulate numerous cellular processes et al. [7] conclusively demonstrate that SIRT7 lacks a sequence-specific DNA including aging, DNA repair, cell SIRT7 is an NAD-dependent deacety- binding motif, it is able to form a com- cycle, metabolism, and survival under lase with high selectivity for the H3K18 plex at the promoters of target genes by stress conditions [1]. Although there acetylation (Ac) mark that functions to associating with the ETS protein ELK4. has been considerable interest in the maintain the transformed phenotype of ELK4-mediated stabilization appears role of Sirtuins in tumorigenesis [1], cancer cells. to be particularly important for gene studies have provided contradictory The studies of Barber et al. show repression in the setting of elevated results with both tumor promoter and that SIRT7 is almost exclusively local- SIRT7 expression, as is seen in cancer. tumor suppressor roles reported [2]. It ized to chromatin, and that it deacety- Consistent with these results, lower appears likely that the different effects lates peptides containing H3K18Ac, H3K18Ac levels are associated with are related to the specific tissue or tumor without activity on 12 other histone overexpression of ELK4 and SIRT7 in type studied, and the models and assay acetylation sites. SIRT7 deacetylase prostate cancer [9]. Finally, this study systems used. activity was abolished by substitu- shows that SIRT7 is necessary for main- Amongst the seven Sirtuins, the tion of a conserved histidine residue tenance of abnormal growth properties in the predicted catalytic domain, or characteristic of cancer cells, including by the Sirtuin inhibitor nicotinamide. anchorage-independent growth and Conversely, SIRT7 overexpression growth in low serum conditions, and Correspondence: Ravi Bhatia induced depletion of H3K18Ac in for tumor formation in xenograft assays. Tel: +1-626-359-8111 ext 62705; Fax: +1-626- 301-8973 cells with negligible changes in other Importantly, in the setting of adenoviral E-mail: [email protected] acetylation marks. Thus, SIRT7 is the E1A oncoprotein-induced transforma- Cell Research | Vol 23 No 1 | January 2013 npg 11 Figure 1 SIRT7 suppresses expression of tumor suppressor genes by locus-specific deacetylation of H3K18Ac at promoter regions. SIRT7 complexes with ELK4 to deacetylate H3K18 at the promoters of a select set of tumor suppressor genes, such as NME1, COPS2, thus repressing target gene expression. SIRT7 may also complex with other as yet undetermined transcriptional proteins (shown as “??”) to deacetylate histone H3K18Ac at promoters of the ribosomal protein gene, RPS7, RPS14, RPS20, which can function as tumor suppressor genes in hematopoietic malignancy, and repress their gene ex- pression. Previously described effects of SIRT7 are also represented. SIRT7 can connect chromatin remodeling complexes with the RNA Pol I machinery required for rDNA driving ribosome biogenesis in dividing cells [6]. SIRT7 is also reported to deacetylate p53, and promote cell survival [3], although this effect needs further confirmation. tion, associated with H3K18 deacety- tions, such as the NME1 and COPS2 SIRT7 may not initiate cellular trans- lation, enhanced cell cycle entry and promoters, but not at others, such as formation by itself. However, studies escape from contact inhibition, SIRT7 the RPS20 promoter. Loss of function evaluating the role of SIRT7 in tumor knockdown restores H3K18Ac and mutations in ribosomal protein genes initiation in cell lines and fibroblasts abolishes the transformed phenotype. have been linked to hematopoietic ma- need to be extended to in vivo evaluation SIRT7 overexpression and SIRT7 gene lignancies [11], and it will be of interest of primary tissues. Finally, development amplification are seen in several tumors, to identify transcriptional regulatory of mice bearing SIRT7 mutant genes and these results support the importance proteins other than ELK4 that can target will be very helpful in defining its role of selective H3K18Ac deacetylation by SIRT7 to specific promoters for H3K18 in epigenetic regulation, stress response, SIRT7 in maintaining transformation of deacetylation. The current studies were and tumor susceptibility, in addition to cancer cells. carried out using cell lines, and it will tumor maintenance as shown here. The results of this study also raise be important to extend these studies to In summary, the studies of Barber several questions, which will be avenues understand the role of SIRT7 in trans- et al. represent a major advance in our for additional investigation in future. formation of primary tumors, and in understanding of the role of Sirtuins in Since H3K18Ac appears to be a general the setting of expression of oncogenes cancer, by demonstrating a novel activ- mark of active transcription [10], it will other than the adenovirus E1A protein. ity of SIRT7 in deacetylating H3K18Ac be of interest to determine the interac- In contrast to its role in maintaining at promoter regions of specific tumor tions between H3K18Ac deacetylation tumor transformation, overexpression suppressor genes, inhibiting transcrip- by SIRT7 and by HDACs in epigenetic of SIRT7 did not lead to oncogenic tion of target genes, and maintaining regulation. ELK4 knockdown leads to transformation of immortalized mouse the malignant phenotype of tumor elevated H3K18Ac levels at some loca- or human fibroblasts, suggesting that cells. This new work supports explora- www.cell-research.com | Cell Research npg 12 tion of a potential therapeutic role for cardiomyocytes and prevents apoptosis terns predict prognosis and treatment restoration of H3K18Ac by targeting and inflammatory cardiomyopathy in response in resectable pancreatic ad- SIRT7. The role of Sirtuins in cancer mice. Circ Res 2008; 102:703-710. enocarcinoma: results from RTOG 4 Voelter-Mahlknecht S, Letzel S, Mahl- 9704. J Clin Oncol 2010; 28:1358- has been the subject of controversy, knecht U. Fluorescence in situ hybrid- 1365. because of its complexity and context ization and chromosomal organization 9 Makkonen H, Jääskeläinen T, Pitkänen- dependence. Together with other recent of the human Sirtuin 7 gene. Int J On- Arsiola T, et al. Identification of ETS- Sirtuin research [12], the present work col 2006; 28:899-908. like transcription factor 4 as a novel supports an important role for Sirtuins in 5 Du J, Zhou Y, Su X, et al. Sirt5 is a androgen receptor target in prostate maintenance of tumorigenic properties NAD-dependent protein lysine dema- cancer cells. Oncogene 2008; 27:4865- of cancer cells and on the front line of lonylase and desuccinylase. Science 4876. cancer research. 2011; 334:806-809. 10 Kurdistani SK, Tavazoie S, Grunstein 6 Tsai YC, Greco TM, Boonmee A, et al. M. Mapping global histone acetylation Functional proteomics establishes the patterns to gene expression. Cell 2004; References interaction of SIRT7 with chromatin 117:721-733. remodeling complexes and expands its 11 Ebert BL, Pretz J, Bosco J, et al. Iden- 1 Liu T, Liu PY, Marshall GM. The criti- role in regulation of RNA polymerase tification of RPS14 as a 5q- syndrome cal role of the class III histone deacety- I transcription. Mol Cell Proteomics gene by RNA interference screen. Na- lase SIRT1 in cancer. Cancer Res 2009; 2012; 11:60-76. ture 2008; 451:335-339. 69:1702-1705. 7 Barber M, Michishita-Kioi E, Xi Y, et 12 Li L, Wang L, Li L, et al. Activation 2 Deng CX. SIRT1, is it a tumor promot- al. SIRT7 links H3K18 deacetylation to of p53 by SIRT1 inhibition enhances er or tumor suppressor? Int J Biol Sci maintenance of oncogenic transforma- elimination of CML leukemia stem 2009; 5:147-52. tion. Nature 2012; 487:114-118. cells in combination with imatinib. 3 Vakhrusheva O, Smolka C, Gajawada P, 8 Manuyakorn A, Paulus R, Farrell J, et Cancer Cell 2012; 21:266-281.
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