Abstract
ARID1A is one of the most frequently mutated epigenetic regulators in a wide spectrum of cancers. Recent studies have shown that ARID1A 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 ARID1A deficiency in promoting cancer progression. Here, 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 a mouse model. In a human cell line model, we found that ARID1A deficiency upregulates the expression of aldehyde dehydrogenase 1 family member A1 (ALDH1A1), 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 ARID1A deficiency increases the accessibility of the enhancer region of ALDH1A1. This study provides the first evidence that ARID1A deficiency promotes pancreatic tumorigenesis by attenuating KRAS-induced senescence through the upregulation of ALDH1A1 expression.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) was the third leading cause of cancer-related death in the United States in 2018 and is projected to become the second leading cause of cancer-related death by 2030 (Rahib et al, 2014)
To identify the mediators that contribute to Arid1a-deficiency-promoted pancreatic intraepithelial neoplasia (PanIN) progression, we followed the PanIN progression in conditional Arid1a knockout mice with mutant Kras (Arid1afl/ fl;Lox-Stop-Lox-KrasG12D/+;Ptf1aCreERT/+, we abbreviate it as AKC) and mice without Arid1a knockout (Arid1a+/+;Lox-Stop-Lox-KrasG12D/+;Ptf1aCreERT/+, we abbreviate it as KC) (Figure 1—figure supplement 2A)
We observed that the lesions dissected from KC and AKC mice were clearly separated in the multidimensional scaling (MDS) plot, and 861 differentially expressed genes (DEGs) (Supplementary file 2), including 532 genes upregulated and 329 genes downregulated in AKC, were identified, which suggests the successful transcriptome profiling of individual PanIN lesions by MATQ-s eq (Figure 1B)
Summary
Pancreatic ductal adenocarcinoma (PDAC) was the third leading cause of cancer-related death in the United States in 2018 and is projected to become the second leading cause of cancer-related death by 2030 (Rahib et al, 2014). Besides the clear driver mutations of PDAC, which include CDKN2A, TP53, SMAD4, and KRAS, there are a large number of genes with low-frequency mutations (Waddell et al, 2015; Bailey et al, 2016; Cancer Genome Atlas Research Network, 2017). It is reasonable to believe that a portion of the low-frequency mutations could be acquired at the early stage and that these mutations could play essential roles in tumorigenesis. Recent studies have shown that ARID1A is necessary to maintain terminal differentiation of pancreatic acinar cells, and knockout of ARID1A results in the accelerated formation of acinar-t o-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) lesions (Zhang, 2018; Livshits et al, 2018; Wang et al, 2019). We found that aldehyde dehydrogenases play an essential role in attenuating senescence by scavenging the reactive oxygen species (ROS) induced by oncogenic KRAS
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