1. Academic Validation
  2. YAP promotes multi-drug resistance and inhibits autophagy-related cell death in hepatocellular carcinoma via the RAC1-ROS-mTOR pathway

YAP promotes multi-drug resistance and inhibits autophagy-related cell death in hepatocellular carcinoma via the RAC1-ROS-mTOR pathway

  • Cancer Cell Int. 2019 Jul 12;19:179. doi: 10.1186/s12935-019-0898-7.
Yuan Zhou  # 1 2 3 4 5 Yubo Wang  # 1 2 3 4 5 Wuhua Zhou 1 2 3 4 5 6 Tianchi Chen 1 2 3 4 5 Qinchuan Wu 1 2 3 4 5 Vikram Kumar Chutturghoon 1 2 3 4 5 Bingyi Lin 1 Lei Geng 1 Zhe Yang 1 Lin Zhou 1 2 3 4 5 Shusen Zheng 1 2 3 4 5


  • 1 1Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
  • 2 2Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou, China.
  • 3 3Key Laboratory of Organ Transplantation, Hangzhou, Zhejiang Province China.
  • 4 4Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou, China.
  • 5 5Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China.
  • 6 6Department of Hepatobiliary and Pancreatic Surgery, Taihe Hospital, Hubei University of Medicine, Hubei, China.
  • # Contributed equally.

Background: Multi-drug resistance is the major cause of chemotherapy failure in hepatocellular carcinoma (HCC). YAP, a critical effector of the Hippo pathway, has been shown to contribute to the progression, metastasis and invasion of cancers. However, the potential role of YAP in mediating drug resistance remains obscure.

Methods: RT-qPCR and western blot were used to assess YAP expression in HCC cell lines. CCK-8 assays, flow cytometry, a xenograft tumour model, immunochemistry and GFP-mRFP-LC3 fusion proteins were utilized to evaluate the effect of YAP on multi-drug resistance, intracellular ROS production and the Autophagy of HCC cells in vitro and in vivo. Autophagy Inhibitor and rescue experiments were carried out to elucidate the mechanism by which YAP promotes chemoresistance in HCC cells.

Results: We found that BEL/FU, a typical HCC cell line with chemoresistance, exhibited overexpression of YAP. Moreover, the inhibition of YAP by shRNA or verteporfin conferred the sensitivity of BEL/FU cells to chemotherapeutic agents through autophagy-related cell death in vitro and in vivo. Mechanistically, YAP silencing significantly enhanced autophagic flux by increasing RAC1-driven ROS, which contributed to the inactivation of mTOR in HCC cells. In addition, the antagonist of Autophagy reversed the enhanced effect of YAP silencing on cell death under treatment with chemotherapeutic agents.

Conclusion: Our findings suggested that YAP upregulation endowed HCC cells with multi-drug resistance via the RAC1-ROS-mTOR pathway, resulting in the repression of autophagy-related cell death. The blockade of YAP may serve as a promising novel therapeutic strategy for overcoming chemoresistance in HCC.


Autophagy-related cell death; Hepatocellular carcinoma; Multi-drug resistance; Yes-associated protein (YAP).