SETD1A augments sorafenib primary resistance via activating YAP in hepatocellular carcinoma
SETD1A augments sorafenib primary resistance via activating YAP in hepatocellular carcinoma
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DOI：
10.1016/j.lfs.2020.118406
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发表时间：
2020-11-01
期刊：
影响因子：
6.1
通讯作者：
Gu, Yan
中科院分区：
文献类型：
--
作者：
Wu, Jugang;Chai, Hongjuan;Gu, Yan
目的：索拉非尼是目前获批的治疗肝细胞癌的一线化疗药物，是有效提高晚期肝细胞癌患者生存率的关键治疗药物。然而，索拉非尼的原发性耐药限制了索拉非尼在HCC治疗中的应用。本研究旨在探讨SETD 1A（Histone Lysine Methyltransferase SET Domain Containing 1A）在索拉非尼原发耐药中的作用及其机制。采用Kaplan-Meier Plotter分析肝癌患者的生存率。进行蛋白质印迹和实时qPCR以分别测量蛋白质和mRNA水平。细胞计数试剂盒-8法和集落形成法测定细胞活力和增殖。碘化丙啶和台盼蓝染色测定进行调查celldeath.Key发现：在这里，我们表明，SETD 1A的表达显着上调，在肝癌细胞系和肿瘤组织相比，正常肝细胞和相应的非肿瘤肝组织，分别。无论是否接受索拉非尼治疗，SETD 1A水平较高的患者总体生存率较低。此外，SETD 1A表达与索拉非尼处理的HCC细胞系的IC 50正相关。此外，我们指出，敲低SETD 1增强索拉非尼诱导的增殖抑制和细胞死亡。SETD 1A缺陷损害雅普（Yes相关蛋白）磷酸化和活化。雅普激活参与了SETD 1A介导的索拉非尼原发性耐药。意义：本研究证实SETD 1A增强雅普激活，诱导肝癌索拉非尼原发性耐药。
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.