Single-PanIN-seq unveils that <i>ARID1A</i> deficiency promotes pancreatic tumorigenesis by attenuating <i>KRAS</i>-induced senescence.

Abstract

ARID1A is one of the most frequently mutated epigenetic regulators in a wide spectrum of cancers. Recent studies have shown that <i>ARID1A</i> deficiency induces global changes in the epigenetic landscape of enhancers and promoters. These broad and complex effects make it challenging to identify the driving mechanisms of <i>ARID1A</i> deficiency in promoting cancer progression. Here, we identified the anti-senescence effect of <i>Arid1a</i> deficiency in the progression of pancreatic intraepithelial neoplasia (PanIN) by profiling the transcriptome of individual PanINs in a mouse model. In a human cell line model, we found that <i>ARID1A</i> deficiency upregulates the expression of aldehyde dehydrogenase 1 family member A1 (<i>ALDH1A1</i>), which plays an essential role in attenuating the senescence induced by oncogenic KRAS through scavenging reactive oxygen species. As a subunit of the SWI/SNF chromatin remodeling complex, our ATAC sequencing data showed that <i>ARID1A</i> deficiency increases the accessibility of the enhancer region of <i>ALDH1A1</i>. This study provides the first evidence that ARID1A deficiency promotes pancreatic tumorigenesis by attenuating <i>KRAS</i>-induced senescence through the upregulation of <i>ALDH1A1</i> expression.