Inhibition of SIRT6 in prostate cancer reduces cell viability and increases sensitivity to chemotherapeutics

Liu, Yewei; Xie, Qian; Wang, Boshi; Shao, Jiaxiang; Zhang, Tingting; Liu, Tengyuan; Huang, Gang; Xia, Weiliang

doi:10.1007/s13238-013-3054-5

Cited by 100 publications

(87 citation statements)

References 24 publications

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“…The anti-apoptotic effect of SIRT6 suggests that it may have potentially oncogenic roles in the tumorigenesis and progression of lung cancer. Our findings support those of a recent report showing that SIRT6 functions as an oncogene in the murine epidermis (38) prostate cancer (39).…”

Section: Discussionsupporting

confidence: 92%

Cyclic AMP Signaling Reduces Sirtuin 6 Expression in Non-small Cell Lung Cancer Cells by Promoting Ubiquitin-Proteasomal Degradation via Inhibition of the Raf-MEK-ERK (Raf/Mitogen-activated Extracellular Signal-regulated Kinase/Extracellular Signal-regulated Kinase) Pathway

Kim

Juhnn

2015

Journal of Biological Chemistry

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Background: cAMP signaling augments radiation-induced apoptosis of lung cancer cells. Results: cAMP signaling reduces the expression of sirtuin 6 deacetylase in non-small cell lung cancer cells by promoting ubiquitin-proteasomal degradation via inhibition of the Raf-MEK-ERK pathway. Conclusion: cAMP signaling reduces sirtuin 6, which augments radiation-induced apoptosis in lung cancer cells. Significance: cAMP signaling augments radiation-induced apoptosis by modulating epigenetic control.

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Section: Discussionsupporting

confidence: 92%

Cyclic AMP Signaling Reduces Sirtuin 6 Expression in Non-small Cell Lung Cancer Cells by Promoting Ubiquitin-Proteasomal Degradation via Inhibition of the Raf-MEK-ERK (Raf/Mitogen-activated Extracellular Signal-regulated Kinase/Extracellular Signal-regulated Kinase) Pathway

Kim

Juhnn

2015

Journal of Biological Chemistry

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“…20,21 Here, we demonstrate that MM cells compensate for genomic instability utilizing mechanisms dependent on SIRT6, which interacts with distinct partners in MM than in other tumors. Specifically, MM cells adapt to ongoing DNA damage via the tripartite SIRT6/ERK2/ELK1 complex, with an associated increase in NHEJ and HR.…”

Section: Discussionmentioning

confidence: 77%

“…15,17,19 Moreover, solid cancers, including breast and prostate cancer, express high levels of SIRT6 and DDR to overcome chemotherapy-induced DNA damage. 20,21 In contrast, SIRT6 appears to be downregulated in other types of solid tumors (ie, gastrointestinal cancers, including colorectal and pancreatic cancer), which results in increased glycolysis, glucose uptake, and MYC activity. 18,22 To date, the role of SIRT6 in hematologic malignancies, including MM, is unknown.…”

Section: Introductionmentioning

confidence: 99%

Evidence for a role of the histone deacetylase SIRT6 in DNA damage response of multiple myeloma cells

Cea

Cagnetta

Adamia

et al. 2016

Blood

101

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Key Points• SIRT6 is highly expressed in multiple myeloma cells and blocks expression of ERKregulated genes.• Targeting SIRT6 enzymatic activity sensitizes multiple myeloma cells to DNAdamaging agents.Multiple myeloma (MM) is characterized by a highly unstable genome, with aneuploidy observed in nearly all patients. The mechanism causing this karyotypic instability is largely unknown, but recent observations have correlated these abnormalities with dysfunctional DNA damage response. Here, we show that the NAD 1 -dependent deacetylase SIRT6 is highly expressed in MM cells, as an adaptive response to genomic stability, and that high SIRT6 levels are associated with adverse prognosis. Mechanistically, SIRT6 interacts with the transcription factor ELK1 and with the ERK signaling-related gene. By binding to their promoters and deacetylating H3K9 at these sites, SIRT6 downregulates the expression of mitogen-activated protein kinase (MAPK) pathway genes, MAPK signaling, and proliferation. In addition, inactivation of ERK2/p90RSK signaling triggered by high SIRT6 levels increases DNA repair via Chk1 and confers resistance to DNA damage. Using genetic and biochemical studies in vitro and in human MM xenograft models, we show that SIRT6 depletion both enhances proliferation and confers sensitization to DNA-damaging agents. Our findings therefore provide insights into the functional interplay between SIRT6 and DNA repair mechanisms, with implications for both tumorigenesis and the treatment of MM. (Blood. 2016;127(9):1138-1150 IntroductionGenomic instability is a common feature of monoclonal gammopathies, resulting in complex genetic changes associated with disease progression from monoclonal gammopathy of undetermined significance to active multiple myeloma (MM) to plasma cell leukemia.1,2 Although alterations in DNA damage checkpoint proteins are less common (10% to 15%) in blood cancers compared with solid tumors, [3][4][5] MM cells do manifest a dysfunctional DNA-damage response (DDR), a key determinant of their genomic instability. [6][7][8] Identifying proteins and signaling pathways that protect MM cells from cumulative genomic instability may therefore lead to innovative therapeutic opportunities, as exemplified by the clinical efficacy of PARP inhibitors in the context of breast and ovarian tumors lacking functional BRCA1 or BRCA2. 9,10 In MM cells, direct evidence of homozygous loss or mutations in BRCA1/2 or other DDR genes is lacking, but increased DNA repair activity has been reported. 11,12 Thus, identification of adaptive pathways for coping with genomic instability in MM may similarly provide the framework for new therapeutic strategies. Sirtuins (SIRTs) are NAD1 -degrading enzymes involved in a variety of biological processes, ranging from metabolism to lifespan regulation. 13,14 Of the 7 sirtuin family members, only SIRT6 clearly contributes to DNA repair. [15][16][17][18] Consistently, murine SIRT6 knockout cells exhibit genomic instability and hypersensitivity to DNA-damaging agents. 15,17,19 Moreover...

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“…Furthermore, SIRT6 downregulation was observed in human pancreatic ductal adenocarcinomas (18), colorectal carcinomas, and head and neck cancers (23). However, SIRT6 has been implicated as an oncogene in skin cancer (11) and prostate cancer (12). SIRT6 is upregulated in human skin cancer, where it promotes skin tumorigenesis by regulating COX-2 expression (11).…”

Section: Discussionmentioning

confidence: 99%

“…SIRT6 also attenuates NF-kB signaling via H3K9 deacetylation, which is an important regulator of aging-related cellular processes (9). Emerging evidence has also implicated SIRT6 in the development of various cancers, including breast cancer (10), skin cancer (11), prostate cancer (12), lung cancer (13), pancreatic cancer (14), and gliomas (15). SIRT6 regulates tumorigenesis by directly interacting with oncogenic proteins or by modulating the acetylation of H3K9 in oncogene promoters (15)(16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

SIRT6 Overexpression Potentiates Apoptosis Evasion in Hepatocellular Carcinoma via BCL2-Associated X Protein–Dependent Apoptotic Pathway

Ran

Chen

Zhang

et al. 2016

Clinical Cancer Research

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Purpose: To characterize the functional role of SIRT6 in hepatocellular carcinoma (HCC).Experimental Design: The expression of SIRT6 in 60 paired paraffin-embedded HCC tissues and adjacent nontumoral liver tissues was examined by immunohistochemistry. The expression of SIRT6 in 101 paired frozen HCC tissues and adjacent nontumoral liver tissues was analyzed by Western blotting analysis and qPCR. The biologic consequences of overexpression and knockdown of SIRT6 in HCC cell lines were studied in vitro and in vivo.Results: SIRT6 expression was frequently upregulated in clinical HCC samples, and its expression was highly associated with tumor grade (P ¼ 0.02), tumor size (P ¼ 0.02), vascular invasion (P ¼ 0.004), and shorter survival (P ¼ 0.024). Depletion of SIRT6 from multiple liver cancer cell lines inhibited their growth and induced apoptosis in vitro. At the molecular level, we observed that the activation of the BCL2-associated X protein (Bax) signaling pathway, a major pathway that determines cancer cell apoptosis, is regulated by SIRT6 via its deacetylase activity. SIRT6 was recruited to the promoter of Bax, where it deacetylated histone 3 lysine 9 and suppressed its promoter activity. Binding of transcription factors (p53 and E2F-1) to Bax promoter was also generally increased in SIRT6-depleted cells. In mouse xenografts, SIRT6 suppression inhibited tumor growth and induced apoptosis. Finally, there is a negative correlation between SIRT6 and Bax mRNA expressions in human HCC samples.Conclusions: SIRT6 is an important protumorigenic factor in liver carcinogenesis. Thus, the therapeutic targeting of SIRT6 may offer options for HCC treatment.

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Inhibition of SIRT6 in prostate cancer reduces cell viability and increases sensitivity to chemotherapeutics

Cited by 100 publications

References 24 publications

Cyclic AMP Signaling Reduces Sirtuin 6 Expression in Non-small Cell Lung Cancer Cells by Promoting Ubiquitin-Proteasomal Degradation via Inhibition of the Raf-MEK-ERK (Raf/Mitogen-activated Extracellular Signal-regulated Kinase/Extracellular Signal-regulated Kinase) Pathway

Cyclic AMP Signaling Reduces Sirtuin 6 Expression in Non-small Cell Lung Cancer Cells by Promoting Ubiquitin-Proteasomal Degradation via Inhibition of the Raf-MEK-ERK (Raf/Mitogen-activated Extracellular Signal-regulated Kinase/Extracellular Signal-regulated Kinase) Pathway

Evidence for a role of the histone deacetylase SIRT6 in DNA damage response of multiple myeloma cells

SIRT6 Overexpression Potentiates Apoptosis Evasion in Hepatocellular Carcinoma via BCL2-Associated X Protein–Dependent Apoptotic Pathway

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