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ARID1A deficiency promotes pancreatic tumorigenesis by reducing KRAS-induced senescence

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE160444 | GEO | 2021/06/04

REPOSITORIES: GEO

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ARID1A deficiency promotes pancreatic tumorigenesis by reducing KRAS-induced senescence (ATAC-Seq)

Project description: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.

2021-06-06 | GSE160440 | GEO

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

2021-06-06 | GSE160443 | GEO

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

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ARID1A deficiency promotes pancreatic tumorigenesis by reducing KRAS-induced senescence

Project description:ARID1A deficiency promotes pancreatic tumorigenesis by reducing KRAS-induced senescence

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

Project description: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.

| S-EPMC8203294 | biostudies-literature

ARID1A deficiency promotes pancreatic tumorigenesis by reducing KRAS-induced senescence (ATAC-Seq)

Project description:ARID1A deficiency promotes pancreatic tumorigenesis by reducing KRAS-induced senescence (ATAC-Seq)

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

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

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

Project description:ARID1A deficiency promotes pancreatic tumorigenesis by reducing KRAS-induced senescence (RNA-Seq II)

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IKBKE Is Required during KRAS-Induced Pancreatic Tumorigenesis.

Project description:Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies lacking effective therapeutic strategies. Here, we show that the noncanonical IκB-related kinase, IKBKE, is a critical oncogenic effector during KRAS-induced pancreatic transformation. Loss of IKBKE inhibits the initiation and progression of pancreatic tumors in mice carrying pancreatic-specific KRAS activation. Mechanistically, we demonstrate that this protumoral effect of IKBKE involves the activation of GLI1 and AKT signaling and is independent of the levels of activity of the NF-κB pathway. Further analysis reveals that IKBKE regulates GLI1 nuclear translocation and promotes the reactivation of AKT post-inhibition of mTOR in PDAC cells. Interestingly, combined inhibition of IKBKE and mTOR synergistically blocks pancreatic tumor growth. Together, our findings highlight the functional importance of IKBKE in pancreatic cancer, support the evaluation of IKBKE as a therapeutic target in PDAC, and suggest IKBKE inhibition as a strategy to improve efficacy of mTOR inhibitors in the clinic. Cancer Res; 77(2); 320-9. ©2017 AACR.

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EGF receptor is required for KRAS-induced pancreatic tumorigenesis.

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