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SIRT7 oncogenic potential in human hepatocellular carcinoma and its regulation by the tumor suppressors mir-125a-5p and mir-125b

Abstract:

Sirtuins are NAD(+) -dependent deacetylases and function in cellular metabolism, stress resistance and ageing. For Sirtuin7 (SIRT7), a role in ribosomal gene transcription is proposed, but its function in cancer has been unclear. In this study, we showed that SIRT7 expression was up-regulated in a large cohort of human hepatocellular carcinoma (HCC) patients. SIRT7 knockdown influenced the cell cycle and caused a significant increase of liver cancer cells to remain in the G1/S phase and to suppress growth. This treatment restored p21(WAF1/Cip1) , induced Beclin-1 and repressed cyclin D1. In addition, sustained suppression of SIRT7 reduced the in vivo tumor growth rate in a mouse xenograft model. To explore mechanisms in SIRT7 regulation, microRNA (miRNA) profiling was carried out. This identified five significantly down-regulated miRNAs in HCC. Bioinformatics analysis of target sites and ectopic expression in HCC cells evidenced miR-125a-5p and miR-125b to suppress SIRT7 and cyclin D1 expression and to induce p21(WAF1/Cip1) -dependent G1 cell cycle arrest. Furthermore, treatment of HCC cells with 5-aza-2'-deoxycytidine or ectopic expression of wild-type but not mutated p53 restored miR-125a-5p and miR-125b expression and inhibited tumor cell growth to suggest their regulation by promoter methylation and p53 activity. To evidence clinical significance of these findings, mutations in the DNA binding domain of p53 and promoter methylation of miR-125b were investigated. Four out of nine patients with induced SIRT7 carried mutations in p53 gene and one patient showed hypermethylation of miR-125b promoter region. Conclusion: Our findings suggest oncogenic potential of SIRT7 in hepatocarcinogenesis. A regulatory loop is proposed whereby SIRT7 inhibits transcriptional activation of p21(WAF1/Cip1) via repression of miR-125a-5p and miR-125b. This makes SIRT7 a promising target in cancer therapy. (HEPATOLOGY 2012.).

23079745

Projects: A3.6: Transcription factor network and links to metabolism in NAFLD

Hepatology
Hepatology 57(3): 1055-67
20th Oct 2012

Jeong Kyu Kim, Ji Heon Noh, Kwang Hwa Jung, Jung Woo Eun, Hyun Jin Bae, Min Gyu Kim, Young Gyoon Chang, Qingyu Shen, Won Sang Park, Jung Young Lee, Jürgen Borlak, Suk Woo Nam

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[Jürgen Borlak]

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Views: 1806
  • Created: 28th Jan 2013 at 13:50
  • Last updated: 24th Oct 2013 at 16:15

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