结直肠癌中APOBEC3G介导HDAC6调控PARP抑制剂药物敏感性的机制研究

组蛋白去乙酰化酶6（HDAC6）在结直肠癌（CRC）高表达且与肿瘤进展密切相关，但HDAC6基因敲除（KO）仅显示部分抗肿瘤效力，机制未明。团队前期借助小分子抑制剂库筛选发现HDAC6KO显著增加CRC细胞对PARP抑制剂的药物敏感性；同时转录组测序发现HDAC6KO上调DNA损伤修复分子APOBEC3G表达。据此推测，HDAC6KO诱导DNA损伤增加，反馈性激活APOBEC3G降低DNA修复压力，若在HDAC6抑制基础上抑制DNA损伤修复反应，则有望成为抗CRC的新型治疗策略。本研究拟观察HDAC6抑制剂ACY1215与PARP抑制剂olaparib对CRC细胞体内外协同抑制效应；探讨HDAC6-APOBEC3G-DNA损伤修复的调控作用机制。本项目将有助于明确APOBEC3G介导HDAC6调控PARP抑制剂药物敏感性的确切机制，为在CRC中探索、开发新型靶向治疗策略提供重要理论基础。

Although histone deacetylase 6 (HDAC6) is highly expressed and correlates with tumor progression in colorectal cancer (CRC), HDAC6 knockout (KO) shows limited efficacy, the mechanism is not clarified yet. In our preliminary work, using small molecular inhibitor library we identified that the sensitivity of PARP inhibitors was dramatically enhanced in CRC cells with HDAC6KO. At the same time, the results from RNA-sequencing show that APOBEC3G, a promoter of DNA damage repair (DDR), was upregulated in CRC cells with HDAC6KO. Therefore, we generate our hypothesis that HDAC6 inhibition induces DNA damage and thereby leads to a feedback upregulation of APOBEC3G to decrease DNA replication stress, and dually targeted inhibition of HDAC6 and DDR means a promising therapeutic strategy in CRC. In the current project, the regulatory axis of HDAC6-APOBEC3G-DDR will be fully investigated; and the synergistic efficacy of HDAC6 selective inhibitor (ACY1215) and PARP inhibitor (olaparib) on CRC cells will be assessed, in vitro and in vivo. This project will validate the hypothesis of HDAC6-APOBEC3G-DDR and contribute to further understanding of the pathogenesis and developing novel therapeutic strategies in CRC.