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      Sirt7 promotes gastric cancer growth and inhibits apoptosis by epigenetically inhibiting miR-34a

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          Abstract

          Gastric cancer is the fourth most common cancer worldwide, with a low 5-year survival rate. Epigenetic modification plays pivotal roles in gastric cancer development. However, the role of histone-modifying enzymes in gastric cancer remains largely unknown. Here we report that Sirt7, a NAD +-dependent class III histone deacetylase, is over-expressed in human gastric cancer tissues. Sirt7 level is significantly correlated with disease stage, metastasis, and survival. Knockdown of Sirt7 in gastric cancer cells inhibits cell proliferation and colony formation in vitro. In vivo subcutaneous xenograft results also show that Sirt7 knockdown can markedly repress gastric cancer cell growth. In addition, Sirt7 depletion induces apoptosis in gastric cancer cells via up-regulating expression of pro-apoptotic proteins and down-regulating anti-apoptotic proteins. Mechanically, Sirt7 binds to the promoter of miR-34a and deacetylases the H3K18ac, thus represses miR-34a expression. Reversely, depletion of miR-34a inhibits gastric cancer apoptosis induced by Sirt7 knockdown, and restores cellular capacity of proliferation and colony formation. miR-34a depletion reduces Sirt7-knockdown-induced arrest of gastric growth . Finally, miR-34a is tightly associated with survival of patients with gastric cancer.

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          Gastric cancer-molecular and clinical dimensions.

          Roopma Wadhwa, Shumei Song, Ju-Seog Lee … (2013)
          Gastric cancer imposes a considerable health burden around the globe despite its declining incidence. The disease is often diagnosed in advanced stages and is associated with a poor prognosis for patients. An in-depth understanding of the molecular underpinnings of gastric cancer has lagged behind many other cancers of similar incidence and morbidity, owing to our limited knowledge of germline susceptibility traits for risk and somatic drivers of progression (to identify novel therapeutic targets). A few germline (PLCE1) and somatic (ERBB2, ERBB3, PTEN, PI3K/AKT/mTOR, FGF, TP53, CDH1 and MET) alterations are emerging and some are being pursued clinically. Novel somatic gene targets (ARID1A, FAT4, MLL and KMT2C) have also been identified and are of interest. Variations in the therapeutic approaches dependent on geographical region are evident for localized gastric cancer-differences that are driven by preferences for the adjuvant strategies and the extent of surgery coupled with philosophical divides. However, greater uniformity in approach has been noted in the metastatic cancer setting, an incurable condition. Having realized only modest successes, momentum is building for carrying out more phase III comparative trials, with some using biomarker-based patient selection strategies. Overall, rapid progress in biotechnology is improving our molecular understanding and can help with new drug discovery. The future prospects are excellent for defining biomarker-based subsets of patients and application of specific therapeutics. However, many challenges remain to be tackled. Here, we review representative molecular and clinical dimensions of gastric cancer.
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            MiR-34, SIRT1 and p53: the feedback loop.

            Munekazu Yamakuchi, Charles J. Lowenstein (2009)
            MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression. Several studies have linked dysregulation of miRNA with tumorigenesis. The TP53 is one of the most commonly mutated genes in human cancers, and its gene product p53 activates transcription of a set of miRNA including the miR-34 family of miRNA. The miR-34 family regulates cell cycle progression, cellular senescence and apoptosis, but the targets of miR-34 are not completely defined. We recently found that miR-34a inhibits SIRT1, a gene that regulates cellular senescence and limits longevity. SIRT1 also regulates p53 dependent apoptosis through deacetylating and stabilizing p53. We also discovered that SIRT1 mediates miR-34a activation of apoptosis by regulating p53 activity. Based on this observation, we propose a positive feedback loop, in which p53 induces expression of miR-34a which suppresses SIRT1, increasing p53 activity.
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              Expression of DBC1 and SIRT1 is associated with poor prognosis of gastric carcinoma.

              Robert Moon, Myoung Ja Chung, S Noh … (2009)
              SIRT1 (silent mating-type information regulation 2 homologue 1) expression has been reported to predict poor survival in some cancers. We therefore investigated the expression levels of SIRT1 and its negative regulator, DBC1 (deleted in breast cancer 1), in gastric cancer patients. We evaluated immunohistochemical expression of DBC1, SIRT1, and p53 using 3-mm tumor cores from 177 gastric cancer patients for tissue microarray. Positive expressions of DBC1 and SIRT1 were seen in 62% (109 of 177) and in 73% (130 of 177) of patients, respectively. Expression of DBC1 was significantly correlated with tumor stage (P = 0.007), lymph node metastasis (P < 0.001), tumor invasion (P = 0.001), venous invasion (P = 0.001), histologic types (P < 0.001), p53 expression (P < 0.001), and SIRT1 expression (P < 0.001). SIRT1 expression was also significantly correlated with tumor stage (P < 0.001), lymph node metastasis (P < 0.001), tumor invasion (P < 0.001), histologic types (P < 0.001), and p53 expression (P = 0.001). In addition, expression of DBC1 was significantly associated with shorter overall survival and relapse-free survival by univariate analysis (P < 0.001 and P < 0.001, respectively). SIRT1 expression was also significantly associated with shorter overall survival and relapse-free survival by univariate analysis (P = 0.001 and P = 0.001, respectively). Multivariate analysis showed that tumor stage and expression of DBC1 were independent prognostic factors significantly associated with overall survival and relapse-free survival. This study shows that expression of DBC1 and SIRT1 is a significant prognostic indicator for gastric carcinoma patients.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Sci Rep
                Journal ID (iso-abbrev): Sci Rep
                Title: Scientific Reports
                Publisher: Nature Publishing Group
                ISSN (Electronic): 2045-2322
                Publication date (Electronic): 10 April 2015
                Publication date Collection: 2015
                Volume: 5
                Electronic Location Identifier: 9787
                Affiliations
                [1 ]Stem Cell Laboratory, Ningbo No.2 Hospital , Ningbo 315010, Zhejiang, China
                [2 ]Gastrointestinal and Hernia Ward, Ningbo No.2 Hospital , Ningbo 315010, Zhejiang, China
                [3 ]Department of Internal Medicine, School of Medicine, Ningbo University , Ningbo 315211, Zhejiang, China
                Author notes
                [*]

                These two authors contributed equally to this work

                Article
                Publisher Item ID: srep09787
                DOI: 10.1038/srep09787
                PMC ID: 4392652
                PubMed ID: 25860861
                SO-VID: a1a03d1c-e64f-43eb-b2ff-621e74b935b6
                Copyright © Copyright © 2015, Macmillan Publishers Limited. All rights reserved
                License:

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder in order to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                Date received : 02 November 2014
                Date accepted : 23 February 2015
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                Subject: Article

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