Research Papers:

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

Xiao-Yang Dai, Lin-Han Zhuang, Dan-Dan Wang, Tian-Yi Zhou, Lin-Lin Chang, Ren-Hua Gai, Di-Feng Zhu, Bo Yang, Hong Zhu _ and Qiao-Jun He

PDF  |  HTML  |  Supplementary Files  |  How to cite

Oncotarget. 2016; 7:6933-6947. https://doi.org/10.18632/oncotarget.6903

Metrics: PDF 2765 views  |   HTML 4256 views  |   ?  


Xiao-Yang Dai1,2,*, Lin-Han Zhuang1,*, Dan-Dan Wang1,*, Tian-Yi Zhou1, Lin-Lin Chang1, Ren-Hua Gai2, Di-Feng Zhu2, Bo Yang1, Hong Zhu1, Qiao-Jun He1

1Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China

2Center 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: [email protected]

Qiao-Jun He, e-mail: [email protected]

Keywords: hepatocellular carcinoma, SN38, hypoxia, resistance, yes-associated protein (YAP)

Received: June 23, 2015     Accepted: December 29, 2015     Published: January 12, 2016


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.

Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.
PII: 6903