化疗耐药是导致肿瘤临床治疗失败的主要原因。DNA损伤修复异常是导致耐药的重要机制，但具体调控机制以及相应策略目前知之甚少。在预实验中，我们发现H3K4甲基化水平在耐药胃癌细胞中下降，抑制H3K4甲基化水平后，可诱导胃癌细胞发生耐药；去甲基化酶KDM5B可去甲基化H3K4，促使XRCC1参与DNA修复；在耐药细胞中, KDM5B被HSP90保护而免受SCF E3连接酶介导的蛋白降解。因此，我们认为HSP90可能通过干扰KDM5B的蛋白降解而维持KDM5B的高表达水平，从而促使H3K4发生去甲基化，招募XRCC1参与DNA修复，最终导致化疗耐药。我们将在本项目中解析KDM5B等蛋白的表达调控机制，阐明KDM5B及其相关分子在DNA损伤修复和胃癌耐药中的作用及其机制，探索靶向干扰HSP90以及KDM5B等分子以抑制或逆转胃癌化疗耐药的可能性，从而为发展有效的肿瘤治疗策略提供新的思路和科学依据。

Cancer cells are featured by genomic instability and simultaneous resistance to various DNA damage-inducing treatments，indicating the deregulated DNA damage response in carcinogenesis. In the preliminary investigations for this application, we found in cisplatin-resistant gastric cancer cells, H3K4 methylation was reduced while KDM5B, the major enzyme to demethylate H3K4, was upregulated. Inhibition of KDM5B significantly reversed the resistance to cisplatin. Interestingly, HSP90 was important to protect KDM5B from ubiquination-proteasome degradation. Inhibition of HSP90 reduced the expression of XRCC1 and KDM5B and significantly increased the sensitivity of gastric cancer cells to cisplatin. Thus, we proposed that HSP90 promotes drug resistance by stabilizing KDM5B to reduce H3K4 methyaltion and recruit XRCC1 from polβ to repair DNA damage. To approve it, we will identify the relevant E3 ligase for polβ, XRCC1 and KDM5B, explore the influence of H3K4 methylation on the recruitment of XRCC1 to damaged DNA. By doing so, we hope we could clarify the role and regulation of KDM5B in DNA damage response and chemoresistance development.