SETD1A augments sorafenib primary resistance via activating YAP in hepatocellular carcinoma.

Sorafenib, the approved first-line chemotherapy drug for HCC (Hepatocellular Carcinoma), remains the key treatment agent which effectively improves the survival rate of advanced HCC patients. However, the sorafenib primary resistance limits the application of sorafenib for HCC treatment. The aims of current study are to explore the role and mechanism of SETD1A (Histone Lysine Methyltransferase SET Domain Containing 1A) in sorafenib primary resistance. The SETD1A expression in HCC was analyzed by Gene Expression Profiling Interactive Analysis. The survival of HCC patients was analyzed by Kaplan-Meier Plotter. Western Blot and Real-time qPCR were performed to measure the protein and mRNA levels, respectively. Cell counting kit-8 assay and colony formation assay were performed to determine cell viability and proliferation. Propidium Iodide and Trypan Blue staining assays were performed to investigate cell death. Here, we showed that the expression of SETD1A was markedly upregulated in both HCC cell lines and tumor tissues compared to normal hepatocytes and corresponding non-tumor liver tissues, respectively. Regardless of whether treated with sorafenib, the patients who had higher level of SETD1A underwent lower survival rate of overall. In addition, SETD1A expression was positively correlated with the IC50 of sorafenib treated HCC cell lines. Furthermore, we indicated that knockdown of SETD1 augmented proliferation inhibition and cell death induced by sorafenib. SETD1A deficiency impaired YAP (Yes-associated protein) phosphorylation and activation. YAP activation contributed to SETD1A mediated sorafenib primary resistance. The current study demonstrated that SETD1A enhanced YAP activation to induce sorafenib primary resistance in HCC.

Wu J ，Chai H ，Li F ，Ren Q ，Gu Y ... -  《-》

Sestrin 2 confers primary resistance to sorafenib by simultaneously activating AKT and AMPK in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the malignancy derived from normal hepatocytes with increasing incidence and extremely poor prognosis worldwide. The only approved first-line systematic treatment agent for HCC, sorafenib, is capable to effectively improve advanced HCC patients' survival. However, it is gradually recognized that the therapeutic response to sorafenib could be drastically diminished after short-term treatment, defined as primary resistance. The present study is aimed to explore the role of stress-inducible protein Sestrin2 (SESN2), one of the most important sestrins family members, in sorafenib primary resistance. Herein, we initially found that SESN2 expression was significantly up-regulated in both HCC cell lines and tissues compared to normal human hepatocytes and corresponding adjacent liver tissues, respectively. In addition, SESN2 expression was highly correlated with sorafenib IC50 of HCC cell lines. Thereafter, we showed that sorafenib treatment resulted in an increase of SESN2 expression and the knockdown of SESN2 exacerbated sorafenib-induced proliferation inhibition and cell apoptosis. Further mechanistic study uncovered that SESN2 deficiency impaired both AKT and AMPK phosphorylation and activation after sorafenib treatment. Moreover, the correlations between SESN2 expression and both phosphor-AKT and phosphor-AMPK expression were illustrated in HCC tissues. Taken together, our study demonstrates that SESN2 activates AKT and AMPK signaling as a novel mechanism to induce sorafenib primary resistance in HCC.

Dai J ，Huang Q ，Niu K ，Wang B ，Li Y ，Dai C ，Chen Z ，Tao K ，Dai J ... -  《-》

Epigenetic regulation of DNA repair gene program by Hippo/YAP1-TET1 axis mediates sorafenib resistance in HCC.

Hepatocellular carcinoma (HCC) is a malignancy that occurs worldwide and is generally associated with poor prognosis. The development of resistance to targeted therapies such as sorafenib is a major challenge in clinical cancer treatment. In the present study, Ten-eleven translocation protein 1 (TET1) was found to be highly expressed in sorafenib-resistant HCC cells and knockdown of TET1 can substantially improve the therapeutic effect of sorafenib on HCC, indicating the potential important roles of TET1 in sorafenib resistance in HCC. Mechanistic studies determined that TET1 and Yes-associated protein 1 (YAP1) synergistically regulate the promoter methylation and gene expression of DNA repair-related genes in sorafenib-resistant HCC cells. RNA sequencing indicated the activation of DNA damage repair signaling was extensively suppressed by the TET1 inhibitor Bobcat339. We also identified TET1 as a direct transcriptional target of YAP1 by promoter analysis and chromatin-immunoprecipitation assays in sorafenib-resistant HCC cells. Furthermore, we showed that Bobcat339 can overcome sorafenib resistance and synergized with sorafenib to induce tumor eradication in HCC cells and mouse models. Finally, immunostaining showed a positive correlation between TET1 and YAP1 in clinical samples. Our findings have identified a previously unrecognized molecular pathway underlying HCC sorafenib resistance, thus revealing a promising strategy for cancer therapy.

Mo C ，You W ，Rao Y ，Lin Z ，Wang S ，He T ，Shen H ，Li X ，Zhang R ，Li B ... -  《-》

Inactivation of hypoxia-induced YAP by statins overcomes hypoxic resistance tosorafenib in hepatocellular carcinoma cells.

Zhou TY ，Zhuang LH ，Hu Y ，Zhou YL ，Lin WK ，Wang DD ，Wan ZQ ，Chang LL ，Chen Y ，Ying MD ，Chen ZB ，Ye S ，Lou JS ，He QJ ，Zhu H ，Yang B ... -  《Scientific Reports》

[YAP regulates the proliferation and modifies the sensitivity to sorafenib in hepatocellular carcinoma cells].

Guo LW ，Shao GL ，Luo J ，Hao WY ，Yao Z ，Zheng JP ... -  《-》