SIRT6 histone deacetylase functions as a potential oncogene in human melanoma

Garcia-Peterson, Liz Mariely; Ndiaye, Mary A.; Singh, Chandra K.; Chhabra, Gagan; Huang, Wei; Ahmad, Nihal

doi:10.18632/genesandcancer.153

Cited by 40 publications

(41 citation statements)

References 45 publications

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“…SIRT6 involvement in autophagy has recently been reported in different cell contexts, including cancer 21 , 32 , 45 . Of note, all the experiments have been performed by using genetic approaches, while no pharmacological modulation of SIRT6 activity have been described.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological activation of SIRT6 triggers lethal autophagy in human cancer cells

Iachettini¹,

Trisciuoglio

Rotili

et al. 2018

Cell Death Dis

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Sirtuin 6 (SIRT6) is a member of the NAD+-dependent class III deacetylase sirtuin family, which plays a key role in cancer by controlling transcription, genome stability, telomere integrity, DNA repair, and autophagy. Here we analyzed the molecular and biological effects of UBCS039, the first synthetic SIRT6 activator. Our data demonstrated that UBCS039 induced a time-dependent activation of autophagy in several human tumor cell lines, as evaluated by increased content of the lipidated form of LC3B by western blot and of autophagosomal puncta by microscopy analysis of GFP-LC3. UBCS039-mediated activation of autophagy was strictly dependent on SIRT6 deacetylating activity since the catalytic mutant H133Y failed to activate autophagy. At the molecular level, SIRT6-mediated autophagy was triggered by an increase of ROS levels, which, in turn, resulted in the activation of the AMPK-ULK1-mTOR signaling pathway. Interestingly, antioxidants were able to completely counteract UBCS039-induced autophagy, suggesting that ROS burst had a key role in upstream events leading to autophagy commitment. Finally, sustained activation of SIRT6 resulted in autophagy-related cell death, a process that was markedly attenuated using either a pan caspases inhibitor (zVAD-fmk) or an autophagy inhibitor (CQ). Overall, our results identified UBCS039 as an efficient SIRT6 activator, thereby providing a proof of principle that modulation of the enzyme can influence therapeutic strategy by enhancing autophagy-dependent cell death.

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Section: Discussionmentioning

confidence: 99%

Pharmacological activation of SIRT6 triggers lethal autophagy in human cancer cells

Iachettini¹,

Trisciuoglio

Rotili

et al. 2018

Cell Death Dis

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“…SIRT6 act as a tumor suppressor in several cancers (38), including pancreatic cancer (39), breast cancer (40), and hepatocellular carcinoma (41,42). While in other cancer types, such as lung cancer (43,44) and melanoma (45), SIRT6 was up-regulated and act as a tumor promoter. In this study.…”

Section: Discussionmentioning

confidence: 99%

Integrative Analysis of Sirtuins and Their Prognostic Significance in Clear Cell Renal Cell Carcinoma

Tan

Peng

et al. 2020

Front. Oncol.

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Sirtuins, class III histone deacetylases, are involved in multiple biological processes in cancer initiation and progression. However, the diverse expression patterns and prognostic values of sirtuins in cancers have yet to be elucidated. In this study, we first evaluated the expression and prognostic values of sirtuins in multiple cancer cohorts using publicly available TCGA pan-cancer datasets. Pan-cancer survival analysis indicated that 6 out of 7 sirtuin family members were significant associated with prognosis of clear cell renal cell carcinoma (KIRC) patients. SIRT1, SIRT3, SIRT4, and SIRT5 were associated with favorable prognosis of KIRC patients, while SIRT6 and SIRT7 were associated with unfavorable prognosis. The expression levels of SIRT4 and SIRT5 in KIRC tissues were lower than that in normal tissues, while SIRT6 and SIRT7 were higher in KIRC tissues. The expression levels of SIRT1, SIRT3, SIRT5, SIRT6, and SIRT7 were significantly correlated with tumor stage and histological grade. DNA methylation may contribute to the dysregulation of sirtuins. Finally, GSEA was conducted to predict the potential functions of sirtuins in KIRC. Our results may provide novel insights for the development of sirtuins-based cancer therapy in KIRC.

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“…However, an oncogenic role of SIRT6 also has been reported in various human cancers. SIRT6 is involved in tumor progression by promoting cell cycle progression and tumor growth ( 16 , 17 ), inhibiting apoptosis ( 18 ), and enhancing EMT-related invasiveness of cancer cells ( 19 , 20 ). In addition, SIRT6 expression is higher in cancer tissue compared with normal tissue in esophagus, thyroid, and melanocytes ( 17 , 18 , 21 ).…”

Section: Introductionmentioning

confidence: 99%

SIRT6 Is Involved in the Progression of Ovarian Carcinomas via β-Catenin-Mediated Epithelial to Mesenchymal Transition

et al. 2018

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SIRT6 is involved in various cellular signaling pathways including those involved in tumorigenesis in association with β-catenin. However, the role of SIRT6 in tumorigenesis has been controversially reported and the studies on the role of SIRT6 in ovarian cancers is limited. In this study, we evaluated the expression and roles of SIRT6 in conjunction with the expression of active β-catenin in 104 human ovarian carcinomas and ovarian cancer cells. In human ovarian carcinomas, the expressions of SIRT6 and active β-catenin were associated with higher tumor stage, higher histologic grade, and platinum-resistance. Moreover, nuclear expression of SIRT6 (104 ovarian carcinomas; P = 0.010, 63 high-grade serous carcinomas; P = 0.040), and activated β-catenin (104 ovarian carcinomas; P = 0.013, 63 high-grade serous carcinomas; P = 0.005) were independent indicators of shorter overall survival of ovarian carcinoma patients in multivariate analysis. In OVCAR3 and OVCAR5 ovarian cancer cells, knock-down of SIRT6 significantly inhibited the migration and invasion of cells, but did not inhibit the proliferation of cells. SIRT6-mediated invasiveness of ovarian cancer cells was associated with the expression of epithelial-to-mesenchymal transition-related signaling molecules such as snail, vimentin, N-cadherin, E-cadherin, and activated β-catenin. Especially, SIRT6-mediated increase of invasiveness and activation of epithelial-to-mesenchymal transition signaling was attenuated by knock-down of β-catenin. In conclusion, this study suggests that SIRT6-β-catenin signaling is involved in the epithelial-to-mesenchymal transition of ovarian cancer cells, and the expression of SIRT6 and active β-catenin might be used as indicators of poor prognosis of ovarian carcinoma patients. In addition, our results suggest that SIRT6-β-catenin signaling might be a new therapeutic target of ovarian carcinomas.

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SIRT6 histone deacetylase functions as a potential oncogene in human melanoma

Cited by 40 publications

References 45 publications

Pharmacological activation of SIRT6 triggers lethal autophagy in human cancer cells

Pharmacological activation of SIRT6 triggers lethal autophagy in human cancer cells

Integrative Analysis of Sirtuins and Their Prognostic Significance in Clear Cell Renal Cell Carcinoma

SIRT6 Is Involved in the Progression of Ovarian Carcinomas via β-Catenin-Mediated Epithelial to Mesenchymal Transition

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