SWI/SNF complex in cancer

Lü, Chao; Allis, C. David

doi:10.1038/ng.3779

Cited by 83 publications

(68 citation statements)

References 14 publications

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“…Deficiency in one or more of these subunits including ARIDIA is associated with enhanced tumor growth and invasiveness [55]. Taken together, 12 genes coding for transcription factors and chromatin modifying proteins that were altered in at least 10% KRAS-mutant tumors.…”

Section: Mutations In Transcription Factors and Chromatin Remodeling mentioning

confidence: 96%

Identification of Subsets of Genetic Alterations in KRAS-mutant Lung Cancer using Association Rule Mining

Tayou¹

2017

Preprint

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Section: Mutations In Transcription Factors and Chromatin Remodeling mentioning

confidence: 96%

Identification of Subsets of Genetic Alterations in KRAS-mutant Lung Cancer using Association Rule Mining

Tayou¹

2017

Preprint

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“…The SWItch/sucrose nonfermentable (SW1/SNF) chromatin remodeling complex promotes DNA access to several transcriptional regulators, including repressors and enhancers, during development . A variety of loss‐ or gain‐of‐function mutations in SWI/SNF subunit genes have been reported to impact on a number of cancers in a highly specific tumor‐ and tissue‐dependent manner . Inactivated SWI/SNF mutation or loss of the AT‐rich interaction domain 1A (ARID1A) subunit is frequently observed in various solid tumors including NB .…”

Section: Introductionmentioning

confidence: 99%

“…11 A variety of loss-or gain-of-function mutations in SWI/SNF subunit genes have been reported to impact on a number of cancers in a highly specific tumor-and tissue-dependent manner. 12 Inactivated SWI/SNF mutation or loss of the AT-rich interaction domain 1A (ARID1A) subunit is frequently observed in various solid tumors including NB. [13][14][15] Emerging data demonstrate that ARID1A interacts with the TERT promoter region to cause chromatin remodeling 16,17 and potentially recruit transcriptional regulators such as the glucocorticoid receptor (GR), 18 histone deacetylase 6 (HDAC6), 19 and SIN3 transcription regulator family member A (SIN3A).…”

mentioning

confidence: 99%

ARID1A‐SIN3A drives retinoic acid‐induced neuroblastoma differentiation by transcriptional repression of TERT

Bui

et al. 2019

Molecular Carcinogenesis

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Aggressive, high‐risk neuroblastoma (NB) exhibits an immature differentiation state, profound epigenetic dysregulation and high telomerase activity. It has been suggested that aggressive NB may be treatable by inducing differentiation whereas therapeutic targeting of telomerase is under investigation for multiple cancer types. While epigenetic regulation of the telomerase reverse transcriptase (TERT) promoter has been described in high‐risk NB, the exact molecular mechanisms are still not completely understood. Here we used quantitative real‐time polymerase chain reaction (PCR), chromatin immunoprecipitation qPCR, quantitative telomeric repeat amplification protocol, and immunoblot techniques to investigate epigenetic regulation of TERT in wild‐type and genetically modified NB cell lines. We demonstrated that TERT expression is reduced during 13‐cis retinoic acid‐induced NB differentiation and that this inversely correlated with increased expression of AT‐rich interaction domain 1A (ARID1A), a subunit of the SWItch/sucrose nonfermentable chromatin remodeling complex. We showed that ARID1A directly caused suppression of TERT and was reliant on DNA binding and co‐occupancy of the TERT promoter by the SIN3 transcription regulator family member A (SIN3A) repressor complex allowing NB differentiation to proceed. Finally, using data from NB patient cohorts, we reported a significant correlation between low ARID1A expression, elevated expression of TERT, and poorly differentiated, high‐risk NB. These results provide insights into a key epigenetic pathway responsible for modulating TERT‐driven NB progression, which could represent a target for therapeutic intervention.

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“…SWI/SNF subunits, particularly AT-rich interactive domain 1 (encoded by the ARID1A), are known to be involved in transcriptional regulation, DNA replication and DNA damage repair 1 . Mutations, translocations and deletions in human cancers lead to defective SWI/SNF complex assembly and recruitment, abnormal gene silencing and tumor development 2,3 . Recent large-scale and integrated multi-platform sequencing analyses of pancreatic cancer ductal adenocarcinoma (PDAC) have revealed ARID1A mutations in ~6% of cases 4 , besides predominant somatic mutations of KRAS, TP53, SMAD4 and CDKN2A.…”

Section: Introductionmentioning

confidence: 99%

Paradoxical role of AT-rich interactive domain 1A in restraining pancreatic carcinogenesis

Ferri-Borgogno

Barui

McGee

et al. 2019

Preprint

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Background & AimsARID1A is postulated to be a tumor suppressor gene owing to loss-of-function mutations in human pancreatic ductal adenocarcinomas (PDAC). However, its role in pancreatic pathogenesis is not clear despite recent studies using genetically engineered mouse (GEM) models. We aimed at further understanding of its direct functional role in PDAC, using a combination of GEM model, PDAC cell lines.MethodsPancreas-specific mutant Arid1a-driven GEM model (Ptf1a-Cre;KrasG12D;Arid1af/f or “KAC”) was generated by crossing Ptf1a-Cre;KrasG12D (“KC”) mice with Arid1af/f mice and characterized histologically with timed necropsies. Arid1a was also deleted using CRISPR-Cas9 system in established PDAC cell lines to study the immediate effects of Arid1a loss in isogenic models. Cells lines with or without Arid1a expression were developed from respective autochthonous PDAC GEM models, compared functionally using various culture assays, and subjected to RNA-sequencing for comparative gene expression analysis. DNA damage repair was analyzed in cultured cells using immunofluorescence and COMET assay.ResultsArid1a is critical for early progression of mutant Kras-driven pre-malignant lesions into PDAC, as evident by lower Ki-67 and higher apoptosis staining in “KAC” as compared to “KC” mice. Enforced deletion of Arid1a in established PDAC cell lines caused suppression of cellular growth and migration, accompanied by compromised DNA damage repair. Despite early development of relatively indolent cystic precursor lesions called intraductal papillary mucinous neoplasms (IPMNs), a subset of “KAC” mice developed aggressive PDAC in later ages. PDAC cells obtained from older autochthonous “KAC” mice revealed epigenetic changes underlying the various compensatory mechanisms to overcome the growth suppressive effects of Arid1a loss.ConclusionsArid1a is an essential survival gene whose loss impairs cellular growth, and thus, its expression is critical during early stages of pancreatic tumorigenesis in mouse models.

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SWI/SNF complex in cancer

Abstract: Four studies in this issue of Nature Genetics report new mechanisms underlying SWI/SNF complex's function in controlling gene expression and suppressing tumor development, providing valuable insights into treating cancers harboring mutations in SWI/SNF complex subunits.

Cited by 83 publications

References 14 publications

Identification of Subsets of Genetic Alterations in KRAS-mutant Lung Cancer using Association Rule Mining

Identification of Subsets of Genetic Alterations in KRAS-mutant Lung Cancer using Association Rule Mining

ARID1A‐SIN3A drives retinoic acid‐induced neuroblastoma differentiation by transcriptional repression of TERT

Paradoxical role of AT-rich interactive domain 1A in restraining pancreatic carcinogenesis

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