SIRT2 overexpression in hepatocellular carcinoma mediates epithelial to mesenchymal transition by protein kinase B/glycogen synthase kinase-3β/β-catenin signaling

Chen, Juan; Chan, Anthony W.H.; To, Ka‐Fai; Chen, Weixian; Zhang, Zhenzhen; Ren, Ji-Hua; Song, Chunli; Cheung, Yu‐San; Lai, Paul B.S.; Cheng, Suk‐Hang; Ng, Margaret H.L.; Huang, Ailong; Ko, Ben C.B.

doi:10.1002/hep.26278

Cited by 193 publications

(154 citation statements)

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“…SIRT1 is essential for proliferation and telomere maintenance (19), whereas SIRT2 mediates the epithelial-mesenchymal transition (EMT) of cancer cells (20). In the present study, we found that SIRT6 was upregulated in a subset of HCC tissues and cell lines.…”

Section: Introductionsupporting

confidence: 51%

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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Section: Introductionsupporting

confidence: 51%

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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“…Previous studies demonstrated that Akt activation inhibits GSK-3b activity, leading to activation of Wnt/b-catenin signaling and the development of stem-like traits and tumor aggressiveness (19,20). Notably, after overexpression of miR-644a in ESCC cells, the levels of PITX2, p-Akt, p-GSK-3b (inactive form) and active-b-catenin were all reduced (Fig.…”

Section: Mir-644a Inhibits Akt/gsk-3b/b-catenin Pathway By Targeting mentioning

confidence: 79%

Downregulation of MicroRNA-644a Promotes Esophageal Squamous Cell Carcinoma Aggressiveness and Stem Cell–like Phenotype via Dysregulation of PITX2

Zhang

Chen

et al. 2017

Clinical Cancer Research

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Purpose: We previously reported the oncogenic role of pairedlike homeodomain 2 (PITX2) in esophageal squamous cell carcinoma (ESCC). In this study, we aimed to identify the miRNA regulators of PITX2 and the mechanism underlying the pathogenesis of ESCC.Experimental Design: Using miRNA profiling and bioinformatics analyses, we identified miR-644a as a negative mediator of PITX2 in ESCC. A series of in vivo and in vitro assays were performed to confirm the effect of miR-644a on PITX2-mediated ESCC malignancy.Results: ESCC cells and tissues expressed less miR-644a than normal epithelial controls. In patient samples, lower expression of miR-644a in ESCC tissues was significantly correlated with tumor recurrence and/or metastasis, such that miR-644a, PITX2, and the combination of the two were independent prognostic indicators for ESCC patient's survival (P < 0.05). Gain-and lossof-function studies demonstrated that miR-644a inhibited ESCC cell growth, migration, and invasion in vitro and suppressed tumor growth and metastasis in vivo. In addition, miR-644a dramatically suppressed self-renewal and stem cell-like traits in ESCC cells. Furthermore, the effect of upregulation of miR-644a was similar to that of PITX2 knockdown in ESCC cells. Mechanistic studies revealed that miR-644a attenuates ESCC cells' malignancy and stem cell-associated phenotype, at least partially, by inactivation of the Akt/GSK-3b/b-catenin signaling pathway through PITX2. Furthermore, promoter hypermethylation caused downregulation of miR-644a in ESCC.Conclusions: Downregulation of miR-644a plays an important role in promoting both aggressiveness and stem-like traits of ESCC cells, suggesting that miR-644a may be useful as a novel prognostic biomarker or therapeutic target for the disease. Clin Cancer Res; 23(1); 298-310. Ó2016 AACR.

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“…14) In contrast, growing evidence suggests that SIRT2 promotes tumorigenesis. [15][16][17][18][19] The reason for this discrepancy is unknown, but it may depend on cancer progression stage or cell type. Recent reports using a selective SIRT2 inhibitor demonstrated that SIRT2 inhibition exhibits anti-tumor activity against breast cancer cells by degrading c-Myc oncoprotein.…”

Section: Resultsmentioning

confidence: 99%

Identification of a Selective SIRT2 Inhibitor and Its Anti-breast Cancer Activity

Shah

Ito

Nakata

et al. 2016

Biological & Pharmaceutical Bulletin

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SIRT2 is a member of the human sirtuin family of proteins and possesses nicotinamide adenine dinucleotide (NAD)-dependent lysine deacetylase activity. SIRT2 has been involved in various cellular processes including gene transcription, genome constancy, and the cell cycle. In addition, SIRT2 is deeply implicated in diverse diseases including cancer. In this study, we identified a small molecule inhibitor of SIRT2 with a structure different from known SIRT2 inhibitors by screening from a chemical library. The hit compound showed a high selectivity toward SIRT2 as it only inhibited SIRT2, and not other sirtuins including SIRT1 and SIRT3 or zinc-dependent histone deacetylases (HDACs) including HDAC1 and HDAC6, in vitro. The compound increased the acetylation level of eukaryotic translation initiation factor 5A (eIF5A), a physiological substrate of SIRT2, and reduced cell viability of human breast cancer cells accompanied with a decrease in c-Myc expression. These results suggest that the compound is cellular effective and has potential for development as a therapeutic agent against breast cancers by specific inhibition of SIRT2.Key words SIRT2; c-Myc; breast cancer; high-throughput screening; eukaryotic translation initiation factor 5ASirtuins are a family of nicotinamide adenine dinucleotide (NAD)-dependent lysine deacetylases shown to play biological and physiological roles in diverse cellular processes such as metabolism, transcription, and DNA repair. Mammals have seven sirtuins that display different subcellular localizations and functions. SIRT2 is a predominantly cytosolic protein and was originally reported as a microtubule deacetylase, 1) but further studies have revealed that SIRT2 acts as a deacetylase for histones and a number of non-histone proteins. This wide variety of substrates might be correlated with physiological roles of SIRT2 in diverse biological processes such as the cell cycle, autophagy, and energy metabolism. 2)Many studies suggest an important involvement of SIRT2 in neurodegeneration, inflammation, bacterial infection, and cancer, and that modulation of SIRT2 activity could be novel strategy for therapies against these disorders.3-5) However, pharmacological evidence for SIRT2 as a valid therapeutic target has not yet been shown. Therefore, potent and selective SIRT2 inhibitors are required for initial proof of concept studies. Although there are several reports describing SIRT2 inhibitors to date, 6) specificity and cellular potency of most present SIRT2 inhibitors appear to be insufficient for elucidating in vivo SIRT2 functions. In this regard, development of potent and highly specific SIRT2 inhibitors has been recently achieved. 7,8) Here, we identified a potent and specific SIRT2 inhibitor by high-throughput screening. Because the fundamental structure of the compound is different from that of existing SIRT2 inhibitors, it may serve as a novel class of chemical tool for exploring SIRT2 functions in cells.

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SIRT2 overexpression in hepatocellular carcinoma mediates epithelial to mesenchymal transition by protein kinase B/glycogen synthase kinase-3β/β-catenin signaling

Cited by 193 publications

References 46 publications

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

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

Downregulation of MicroRNA-644a Promotes Esophageal Squamous Cell Carcinoma Aggressiveness and Stem Cell–like Phenotype via Dysregulation of PITX2

Identification of a Selective SIRT2 Inhibitor and Its Anti-breast Cancer Activity

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