SAHA逆转ERCC1高表达肿瘤对铂耐药的研究

Recent studies showed tumors with exeision repair cross completion gene1(ERCC1) high expression could produce platinum resistance. ERCC1 and xeroderma pigmentosum pomplementary group F(XPF) constitute ERCC1-XPF heterodimer, have important roles in the mucleotide excision repair(NER). In our studies found Vorinostat(SAHA) enhanced sensitivity to platinum in human lung adenocarcinoma A549 cells with ERCC1 positive expression, however the mechanism is not clear. There are many lysine in the ERCC1 and XPF binding HhH2 domains, and SAHA could enhance lysine acetylation. Therefore, we hypothesis that SAHA could inhibite ERCC1 activity by lysine acetylation in HhH2 domains. We will investigate the SAHA overcoming platimum resistance in vivo and in vitro, in order to provide scientific evidence for chemotherapy overcoming platimum resistance in these patients.

近来研究表明DNA切除修复交叉互补基因1 (ERCC1)高表达肿瘤会对铂产生耐药性。ERCC1与着色性干皮病F（XPF）因子相互结合组成ERCC1-XPF异二聚体，在核苷酸切除修复(nucleotide excision repair，NER)过程中起着重要作用。前期研究中我们发现，Vorinostat (SAHA)可以增强铂对ERCC1表达的人肺腺癌A549的细胞毒作用，但其作用机制有待探讨。由于 ERCC1-XPF相互结合的HhH2域有多个赖氨酸位点，而SAHA可以乙酰化修饰赖氨酸，因此我们推测SAHA可通过乙酰化修饰ERCC1的HhH2域赖氨酸从而抑制其活性。本研究拟通过体内外实验探讨SAHA逆转高表达ERCC1肿瘤对铂耐药的可行性和有效性，为铂耐药患者的化疗方案提供科学理论依据。

DNA切除修复交叉互补基因1 (ERCC1)高表达肿瘤会对铂产生耐药性, 本研究通过体内、外实验证明了组蛋白去乙酰化酶抑制剂SAHA增强ERCC1高表达肺癌对顺铂的敏感性，并且分析了SAHA增强铂耐药敏感性的ERCC1介导的细胞内机制，阐明了SAHA激活E2F1，诱导MiR-149抑制ERCC1表达的分子机制，为肺癌铂耐药的患者提供了理论依据。