Role of BAP1 in pancreatic cancer (ChIP-seq Human)

We found that BAP1 (BRCA1 Associated Protein-1) shows loss of heterozygosity in over 25% of pancreatic cancer patients and functions as tumor suppressor. Conditional deletion of Bap1 in murine pancreas led to genomic instability, accumulation of DNA damage, and an inflammatory response that evolved to pancreatitis with full penetrance. Concomitant expression of oncogenic KrasG12D led to malignant transformation and development of invasive and metastatic pancreatic cancer. At the molecular level, BAP1 maintains the integrity of the exocrine pancreas by regulating genomic stability and its loss confers sensitivity to radio- and platinum-based therapies. Overall design: PANC1 and HPDE cells were treated with 10Gy of IR. One hour later cells were fixed and analyzed by ChIP-seq for BAP1 and H2AK119ub.

我们发现，BRCA1相关蛋白1（BRCA1 Associated Protein-1，BAP1）在超过25%的胰腺癌患者中存在杂合性缺失，并发挥肿瘤抑制因子的功能。在小鼠胰腺中条件性敲除Bap1可引发基因组不稳定、DNA损伤蓄积，以及可完全外显并进展为胰腺炎的炎症反应。在该背景下同时表达致癌性KrasG12D可诱导恶性转化，并发展为侵袭性及转移性胰腺癌。在分子层面，BAP1通过调控基因组稳定性维持外分泌胰腺的完整性；其缺失会使肿瘤对放射治疗及铂类药物治疗产生敏感性。实验整体设计：将PANC1与HPDE细胞施以10Gy电离辐射（Ionizing Radiation，IR），1小时后固定细胞，并通过染色质免疫沉淀测序（ChIP-seq）检测BAP1与H2AK119ub的结合情况。