HDAC5通过去乙酰化Ku70调控胰腺癌对PARP抑制剂敏感性的机制研究

PARP抑制剂对于BRCA基因突变的转移性胰腺癌的治疗效果令人振奋，但胰腺癌病人的BRCA基因突变率低（3-5%），PARP抑制剂应用范围有限。HDAC5在多种实体肿瘤中低表达，且显著地影响了胰腺癌病人的预后。申请人发现，HDAC5的敲低或者药物抑制显著增加了胰腺癌细胞对于PARP抑制剂的敏感性；HDAC5敲低显著增加了NHEJ活性而抑制了HR通路活性；HDAC5可与Ku70互作并介导Ku70的去乙酰化。鉴于Ku70的乙酰化对于Ku70在DNA双键断裂处的募集及NHEJ通路的活性具有重要意义，申请人假设HDAC5通过介导Ku70去乙酰化调控NHEJ及HR的活性；而HDAC5缺失或者HDAC5的靶向抑制可增加胰腺癌细胞对于PARP抑制剂的敏感性。本研究将阐述HDAC5调控DNA双键断裂修复的具体机制，并为临床提供增敏PARP抑制剂治疗的新思路。

PARP inhibitor has an impressing effect on metastatic pancreatic cancer patients with germinal BRCA gene mutation. Owing to the limited mutation rate of BRCA gene in PDAC (3-5%), few patients benefit from PARPi treatment in clinic. HDAC5 is frequently downregulated in multiple cancer types and significantly influenced the prognosis of PDAC patients. Applicant found that HDAC5 knock-down or targeted inhibition increased NHEJ activity and inhibited HR activity, and dramatically increased the vulnerability to PARPi in PDAC cell lines; further investigation found that HDAC5 interacts with Ku70 and mediates the deacetylation of Ku70. It's been reported that Ku70 acetylation is important for its recruiment to DSB sites and its function in NHEJ. Thus, applicant assume that HDAC5 regulates NHEJ & HR activity via Ku70 deacetylation; the deletion or targeted inhibition of HDAC5 would sensitize PDAC cells to PARPi. This project would demonstrate the mechanism of HDAC5's regulation on DSB repair and provide a viable strategy to sensitize PDAC cells to PARP inhibitor.