Single-PanIN-seq unveils that ARID1A deficiency promotes pancreatic tumorigenesis by attenuating KRAS-induced senescence

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 drivin...

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Autores principales:	Shou Liu, Wenjian Cao, Yichi Niu, Jiayi Luo, Yanhua Zhao, Zhiying Hu, Chenghang Zong
Formato:	article
Lenguaje:	EN
Publicado:	eLife Sciences Publications Ltd 2021
Materias:	ARID1A SWI/SNF complex senescence ALDH PanIN-seq pancreatic cancer Medicine R Science Q Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/2e2a470b93b44589b23f447e74af6bb3
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spelling	oai:doaj.org-article:2e2a470b93b44589b23f447e74af6bb32021-11-25T14:36:11ZSingle-PanIN-seq unveils that ARID1A deficiency promotes pancreatic tumorigenesis by attenuating KRAS-induced senescence10.7554/eLife.642042050-084Xe64204https://doaj.org/article/2e2a470b93b44589b23f447e74af6bb32021-05-01T00:00:00Zhttps://elifesciences.org/articles/64204https://doaj.org/toc/2050-084XARID1A 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.Shou LiuWenjian CaoYichi NiuJiayi LuoYanhua ZhaoZhiying HuChenghang ZongeLife Sciences Publications LtdarticleARID1ASWI/SNF complexsenescenceALDHPanIN-seqpancreatic cancerMedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	ARID1A SWI/SNF complex senescence ALDH PanIN-seq pancreatic cancer Medicine R Science Q Biology (General) QH301-705.5
spellingShingle	ARID1A SWI/SNF complex senescence ALDH PanIN-seq pancreatic cancer Medicine R Science Q Biology (General) QH301-705.5 Shou Liu Wenjian Cao Yichi Niu Jiayi Luo Yanhua Zhao Zhiying Hu Chenghang Zong Single-PanIN-seq unveils that ARID1A deficiency promotes pancreatic tumorigenesis by attenuating KRAS-induced senescence
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.
format	article
author	Shou Liu Wenjian Cao Yichi Niu Jiayi Luo Yanhua Zhao Zhiying Hu Chenghang Zong
author_facet	Shou Liu Wenjian Cao Yichi Niu Jiayi Luo Yanhua Zhao Zhiying Hu Chenghang Zong
author_sort	Shou Liu
title	Single-PanIN-seq unveils that ARID1A deficiency promotes pancreatic tumorigenesis by attenuating KRAS-induced senescence
title_short	Single-PanIN-seq unveils that ARID1A deficiency promotes pancreatic tumorigenesis by attenuating KRAS-induced senescence
title_full	Single-PanIN-seq unveils that ARID1A deficiency promotes pancreatic tumorigenesis by attenuating KRAS-induced senescence
title_fullStr	Single-PanIN-seq unveils that ARID1A deficiency promotes pancreatic tumorigenesis by attenuating KRAS-induced senescence
title_full_unstemmed	Single-PanIN-seq unveils that ARID1A deficiency promotes pancreatic tumorigenesis by attenuating KRAS-induced senescence
title_sort	single-panin-seq unveils that arid1a deficiency promotes pancreatic tumorigenesis by attenuating kras-induced senescence
publisher	eLife Sciences Publications Ltd
publishDate	2021
url	https://doaj.org/article/2e2a470b93b44589b23f447e74af6bb3
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Single-PanIN-seq unveils that ARID1A deficiency promotes pancreatic tumorigenesis by attenuating KRAS-induced senescence

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