Nuclear translocation and activation of YAP by hypoxia contributes to the chemoresistance of SN38 in hepatocellular carcinoma cells

// Xiao-Yang Dai 1, 2, * , Lin-Han Zhuang 1, * , Dan-Dan Wang 1, * , Tian-Yi Zhou 1 , Lin-Lin Chang 1 , Ren-Hua Gai 2 , Di-Feng Zhu 2 , Bo Yang 1 , Hong Zhu 1 , Qiao-Jun He 1 1 Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China 2 Center for Drug Safety Evaluation and Research of Zhejiang University, Hangzhou 310058, China * These authors contributed equally to this work Correspondence to: Hong Zhu, e-mail: hongzhu@zju.edu.cn Qiao-Jun He, e-mail: qiaojunhe@zju.edu.cn Keywords: hepatocellular carcinoma, SN38, hypoxia, resistance, yes-associated protein (YAP) Received: June 23, 2015 Accepted: December 29, 2015 Published: January 12, 2016 ABSTRACT Although hypoxia is a prominent feature contributing to the therapeutic resistance of hepatocellular carcinoma cells (HCC) against chemotherapeutic agents, including the Topoisomerase I inhibitor SN38, the underlying mechanism is not fully understood and its understanding remains a major clinical challenge. In the present study, we found that hypoxia-induced nuclear translocation and accumulation of YAP acted as a survival input to promote resistance to SN38 in HCC. The induction of YAP by hypoxia was not mediated by HIF-1α because manipulating the abundance of HIF-1α with CoCl2, exogenous expression, and RNA interference had no effect on the phosphorylation or total levels of YAP. The mevalonate-HMG-CoA reductase (HMGCR) pathway may modulate the YAP activation under hypoxia. Combined YAP inhibition using either siRNA or the HMGCR inhibitor statins together with SN38 treatment produced improved anti-cancer effects in HCC cells. The increased anti-cancer effect of the combined treatment with statins and irinotecan (the prodrug of SN-38) was further validated in a human HepG2 xenograft model of HCC in nude mice. Taken together, our findings identify YAP as a novel mediator of hypoxic-resistance to SN38. These results suggest that the administration of SN28 together with the suppression of YAP using statins is a promising strategy for enhancing the treatment response in HCC patients, particularly in advanced stage HCC cases presenting hypoxic resistance.