ARID1A deficiency promotes pancreatic tumorigenesis by reducing KRAS-induced senescence (RNA-Seq I). ARID1A deficiency promotes pancreatic tumorigenesis by reducing KRAS-induced senescence (RNA-Seq I)

ARID1A is one of the most frequently mutated epigenetic regulators in a wide spectrum of cancers. In this study, we identified the anti-senescence effect of ARID1A deficiency in the progression of pancreatic intraepithelial neoplasia (PanIN) by profiling the transcriptome of individual PanINs in the mouse model. Interestingly, we found that ARID1A deficiency activates the transcription of Aldehyde dehydrogenase 1 family, member A1 (ALDH1A1), which play essential roles in attenuating the senescence by significantly reducing reactive oxygen species (ROS) induced by oncogenic KRAS. Our findings further suggest that ALDH could be considered as a potential adjuvant target for prevention and treatment of pancreatic cancer. Overall design: We performed RNA-seq on wild type HPNE cell line and ARID1A-KO HPNE cell line with and without KRAS overexpression. Three biological replicates per group.

ARID1A是在多种癌症类型中最常发生突变的表观遗传调控因子之一。本研究通过对小鼠模型中的单个胰腺上皮内瘤变（pancreatic intraepithelial neoplasia, PanIN）进行转录组分析，明确了ARID1A缺失在胰腺上皮内瘤变进展过程中的抗细胞衰老作用。有趣的是，我们发现ARID1A缺失会激活乙醛脱氢酶1家族成员A1（ALDH1A1）的转录，该蛋白可通过显著降低致癌性KRAS诱导产生的活性氧（reactive oxygen species, ROS），在延缓细胞衰老过程中发挥关键作用。本研究结果进一步提示，ALDH可作为预防与治疗胰腺癌的潜在辅助治疗靶点。实验整体设计：我们对分别存在或不存在KRAS过表达的野生型HPNE细胞系与ARID1A基因敲除型HPNE细胞系进行了RNA测序（RNA-seq），每组设置3次生物学重复。