Sirtuin7 oncogenic potential in human hepatocellular... : Hepatology (original) (raw)

Hepatobiliary Malignancies

Sirtuin7 oncogenic potential in human hepatocellular carcinoma and its regulation by the tumor suppressors MiR-125a-5p and MiR-125b

Kim, Jeong Kyu1,2; Noh, Ji Heon1,2; Jung, Kwang Hwa1,2; Eun, Jung Woo1,2; Bae, Hyun Jin1,2; Kim, Min Gyu1,2; Chang, Young Gyoon1,2; Shen, Qingyu1,2; Park, Won Sang1,2; Lee, Jung Young1,2; Borlak, Jürgen3; Nam, Suk Woo1,2,*,#

1_Department of Pathology, College of Medicine, Catholic University of Korea, Seoul, Korea_

2_Functional RNomics Research Center, Catholic University of Korea, Seoul, Korea_

3_Center of Pharmacology and Toxicology, Hannover Medical School, Hannover, Germany_

*Address reprint requests to: Department of Pathology, College of Medicine and Functional RNomics Research Center, Catholic University of Korea, Banpo-dong #505, Seocho-gu, South Korea 137–701

Email: [email protected]

Received 21 May 2012; Accepted 28 September 2012

Grant sponsor: National Research Foundation of Korea (NRF); Grant sponsor: Korean government (MEST); Grant Number: 2011–0010705; Grant sponsor: Korean Ministry of the Environment “The Converging-Technology project”; Grant Number: 212 101 003; Grant sponsor: Korean Science and Engineering Foundation via the “Cancer Evolution Research Center” at the Catholic University of Korea; Grant Number: 2012047939.

Potential conflict of interest: Nothing to report.

#fax: +82–2–537–6586

Abstract

Sirtuins are nicotinamide adenine dinucleotide oxidized form (NAD+)-dependent deacetylases and function in cellular metabolism, stress resistance, and aging. For sirtuin7 (SIRT7), a role in ribosomal gene transcription is proposed, but its function in cancer has been unclear. In this study we show 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 p21WAF1/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 showed that miR-125a-5p and miR-125b suppressed SIRT7 and cyclin D1 expression and induced p21WAF1/Cip1-dependent G1 cell cycle arrest. Furthermore, treatment of HCC cells with 5-aza-2′-deoxycytidine or ectopic expression of wildtype but not mutated p53 restored miR-125a-5p and miR-125b expression and inhibited tumor cell growth, suggesting their regulation by promoter methylation and p53 activity. To show the 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 the p53 gene and one patient showed hypermethylation of the miR-125b promoter region. Conclusion: Our findings suggest the oncogenic potential of SIRT7 in hepatocarcinogenesis. A regulatory loop is proposed whereby SIRT7 inhibits transcriptional activation of p21WAF1/Cip1 by way of repression of miR-125a-5p and miR-125b. This makes SIRT7 a promising target in cancer therapy. (Hepatology 2013)