Jugang Wu1, Hongjuan Chai2, Feng Li1, Qing Ren3, Yan Gu4. 1. Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China. 2. Department of Gynecology and Obstetrics, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China. 3. Department of Gynecology and Obstetrics, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China; Department of Gynecology and Obstetrics, Hainan West Central Hospital (Shanghai Ninth People's Hospital, Hainan Branch), Shanghai JiaoTong University School of Medicine, Hainan, China. Electronic address: renq275@126.com. 4. Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China. Electronic address: yangu@sjtu.edu.cn.
Abstract
AIMS: 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. MAIN METHODS: 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. KEY FINDINGS: 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. SIGNIFICANCE: The current study demonstrated that SETD1A enhanced YAP activation to induce sorafenib primary resistance in HCC.
AIMS: 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. MAIN METHODS: 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. KEY FINDINGS: 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. SETD1Adeficiency impaired YAP (Yes-associated protein) phosphorylation and activation. YAP activation contributed to SETD1A mediated sorafenib primary resistance. SIGNIFICANCE: The current study demonstrated that SETD1A enhanced YAP activation to induce sorafenib primary resistance in HCC.
Authors: Rui Wang; Jian Liu; Kai Li; Ganghua Yang; Sisi Chen; Jie Wu; Xinming Xie; Hong Ren; Yamei Pang Journal: J Exp Clin Cancer Res Date: 2021-10-13