SETD1A augments sorafenib primary resistance via activating YAP in hepatocellular carcinoma

Abstract

Background: Sorafenib, the approved first-line chemotherapy drug for HCC, remains the key treatment agent which can effectively improve 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. Methods: The expression of SETD1A in HCC was analyzed by Gene Expression Profiling Interactive Analysis. The survival of HCC patients was analyzed by KM plotter: 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. Results: 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. The patients who had higher level of SETD1A underwent lower survival rate of overall and sorafenib treated HCC patients, respectively. 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 phosphorylation and activation. YAP activation contributed to SETD1A mediated sorafenib primary resistance. Conclusions: Taken together, the current study demonstrated that STED1A enhanced YAP activation to induce sorafenib primary resistance in HCC.

ZNF382 inhibits hepatocellular carcinoma (HCC) cell proliferation and motility and induces apoptosis by up-regulating SOX11

“…Therefore, early diagnosis and precise treatment of HCC are crucial [4]. The main causes of HCC include hepatitis B and C virus infection, aflatoxin, liver cirrhosis, and sex hormones [5]. The early clinical symptoms of HCC are not obvious, and the main clinical symptoms are pain and fatigue in the liver area, etc., which are often in the advanced stage, leading to poor prognosis [6].…”