miR-592/WSB1/HIF-1α axis inhibits glycolytic metabolism to decrease hepatocellular carcinoma growth

// Yan-Yan Jia 1, 2, * , Jin-Yi Zhao 2, * , Bing-Ling Li 1, * , Kai Gao 2, * , Ying Song 2 , Mei-You Liu 2 , Xiao-Juan Yang 2 , Yan Xue 3 , Ai-Dong Wen 2 , Lei Shi 1 1 Department of Pharmacy, General Hospital of Guangzhou Military Command of People’s Liberation Army, Guangzhou, Guangdong, P. R. China 2 Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, P. R. China 3 Department of Oncology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, P. R. China * These authors have contributed equally to this work Correspondence to: Lei Shi, email: xjyypharmacy@126.com Ai-Dong Wen, email: adwen-2004@hotmail.com Yan Xue, email: 25961754@qq.com Keywords: hepatocellular carcinoma, miR-592, hypoxia inducible factor-1α, glycolysis, WSB1 Received: December 17, 2015 Accepted: April 02, 2016 Published: May 2, 2016 ABSTRACT Hepatocellular carcinoma (HCC) cells rapidly switch their energy source from oxidative phosphorylation to glycolytic metabolism in order to efficiently proliferate. However, the molecular mechanisms responsible for this switch remain unclear. In this study, we found that miR-592 was frequently downregulated in human HCC tissues and cell lines, and its downregulation was closely correlated with aggressive clinicopathological features and poor prognosis of HCC patients. Overexpression of miR-592 inhibited aerobic glycolysis and proliferation in HCC cells in vitro . Conversely, knockdown of miR-592 promoted HCC growth in both subcutaneous injection and orthotopic liver tumor implantation models in vivo . Mechanistically, miR-592 downregulation in human HCCs was correlated with an upregulation of WD repeat and SOCS box containing 1 (WSB1). We further showed that miR-592 directly binds to the 3’-UTR of the WSB1 gene, thus disrupting hypoxia inducible factor-1α (HIF-1α) protein stabilization. In turn, overexpression of WSB1 in HCC cells rescued decreased HIF-1α expression, glucose uptake, and HCC growth induced by miR-592. Collectively, our clinical data and functional studies suggest that miR-592 is a new robust inhibitor of the Warburg effect and a promising therapeutic target for HCC treatment.