MiR424 and the CBX4 inhibitor UNC3866 Efficiently Suppress YAP Nucleus Translocation in Hepatocellular Carcinoma Cells to Protect Against Sorafenib Resistance

Against the response to sorafenib resistance (SR) and increasing the efficiency of drug therapy represent the clinical challenge in Hepatocellular carcinoma (HCC) therapy. This study aimed to investigate the possible role of inhibiting miR424 and CBX4 by deregulating cancer stem cells (CSCs) characters which contribute to SR in advanced HCC. We analyzed the effect of miR424 on CSC characteristics using HCC cell lines and a xenograft mouse model with resistance to sorafenib. The results demonstrated that miR424 suppressed its direct target CBX4, which is significantly associated with stem-cell-like properties, poor survival and clinical characteristics. Furthermore, CBX4 induced nuclear translocation of YAP protein but was not associated with protein production. When YAP1 and CBX4 were modulated either alone or together in SR tumors with CA3 and UNC3866, respectively, tumorigenicity and stem-like properties were extremely inhibited. It indicated that these compounds exerted a strong antitumor effect in vivo against SR HCC cells. Thus, Blocking the crosstalk between CBX4 and YAP1 is critical in response to sorafenib resistance, and it could be a promising therapeutic strategy for patients with advanced HCC. Funding Statement: This study was funded by the National Natural Science Foundation of China (81872025，81460360 and 81772632), the Beijing Natural Science Foundation (7182030), the Clinical Features Research of Capital (No. Z151100004015173) and Natural Science Foundation of Xinjiang Uygur Autonomous Region (2015211C126). The grant from Scientific Research Foundation for Returned Scholars, Peking University Third Hospital (No. Y76476-05). Declaration of Interests: The authors declare that there are no conflicts of interest. Ethics Approval Statement: The acquisition and use of the utilized tissues were permitted based on the acquisition of informed consent according to the protocol approved by the Ethics Committee.