ARID1B, a member of the human SWI/SNF chromatin remodeling complex, exhibits tumour-suppressor activities in pancreatic cancer cell lines

Khursheed, Mohammed; Kolla, Jayaprakash Narayana; Kotapalli, Viswakalyan; Gupta, Neha A; Gowrishankar, Swarnalata; Uppin, Shantveer G; Sastry, R A; Koganti, Suman B; Sundaram, Curam Sreenivasacharlu; Pollack, Jonathan R.; Bashyam, Murali D.

doi:10.1038/bjc.2013.200

Cited by 60 publications

(69 citation statements)

References 37 publications

(50 reference statements)

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“…ARID1B is a tumor suppressor, mutated by deletion, in neuroblastoma (Sausen et al, 2013). The ARID1B promoter can be hyper-methylated, resulting in decreased ARID1B expression, as in pancreatic cancer cells (Khursheed et al, 2013). Arid1b also functions as a tumor suppressor in the context of Nf1 loss, with low expression in neurofibromas resulting in increased β-catenin, Wnt/β-catenin target gene expression, and tumorigenesis (Figure 6).…”

Section: Discussionmentioning

confidence: 99%

Insertional Mutagenesis Identifies a STAT3/Arid1b/β-catenin Pathway Driving Neurofibroma Initiation

Keng

Patmore

et al. 2016

Cell Reports

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Summary To identify genes and signaling pathways that initiate Neurofibromatosis type 1 (Nf1) neurofibroma, we used unbiased insertional mutagenesis screening, mouse models, and molecular analyses. We mapped an Nf1-Stat3-Arid1b/β-catenin pathway which becomes active in the context of Nf1 loss. Genetic deletion of Stat3 in Schwann cells progenitors (SCPs) and Schwann cells (SCs) prevents neurofibroma formation, decreasing SCP self-renewal and β-catenin activity. β-catenin expression rescues effects of Stat3 loss in SCPs. Importantly, P-STAT3 and β-catenin expression correlate in human neurofibromas. Mechanistically, P-Stat3 represses Gsk3β and the SWI/SNF gene Arid1b, to increase β-catenin. Knock-down of Arid1b or Gsk3β in Stat3fl/f;Nf1fl/fl;DhhCre SCPs rescues neurofibroma formation after in vivo transplantation. Stat3 represses Arid1b through histone modification in a Brg1 dependent manner, indicating that epigenetic modification plays a role in early tumorigenesis. Our data map a neural tumorigenesis pathway, and support testing JAK/STAT and Wnt/β-catenin pathway inhibitors in neurofibroma therapeutic trials.

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Section: Discussionmentioning

confidence: 99%

Insertional Mutagenesis Identifies a STAT3/Arid1b/β-catenin Pathway Driving Neurofibroma Initiation

Keng

Patmore

et al. 2016

Cell Reports

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“…The apparent reasoning behind this was that based on his germline ARID1B mutation and inferred CSS diagnosis, he was thought to be susceptible to infection and based on the findings of somatic ARID1B mutations in cancer [Stephens et al, 2012;Kadoch et al, 2013;Khursheed et al, 2013;Cajuso et al, 2014] he was considered at an increased risk of neoplasia. Immunodeficiencies have been reported in other ID syndromes, such as the 22q11 deletion syndrome.…”

Section: Article American Journal Of Medical Genetics Part C (Seminarmentioning

confidence: 99%

The ARID1B phenotype: What we have learned so far

Santen

Clayton‐Smith²

2014

American J of Med Genetics Pt C

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Evidence is now accumulating from a number of sequencing studies that ARID1B not only appears to be one of the most frequently mutated intellectual disability (ID) genes, but that the range of phenotypes caused by ARID1B mutations seems to be extremely wide. Thus, it is one of the most interesting ID genes identified so far in the exome sequencing era. In this article, we review the literature surrounding ARID1B and attempt to delineate the ARID1B phenotype. The vast majority of published ARID1B patients have been ascertained through studies of Coffin-Siris syndrome (CSS), which leads to bias when documenting the frequencies of phenotypic features. Additional observations of those individuals ascertained through exome sequencing studies helps in delineation of the broader clinical phenotype. We are currently establishing an ARID1B consortium, aimed at collecting ARID1B patients identified through genome-wide sequencing strategies. We hope that this endeavor will eventually lead to a more comprehensive view of the ARID1B phenotype.

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“…The BAF subunit ARID1A has the highest mutation rate among SWI/SNF components (Helming et al 2014a). Mutations in its paralog, ARID1B, are less frequent but have also been observed in melanoma, gastric cancer, colorectal cancer, HCC, neuroblastoma, and pancreatic cancer (Fujimoto et al 2012;Khursheed et al 2013;Sausen et al 2013;Lee et al 2015). In HCC, >20% of the tumors present alterations in SWI/SNF components, and mutations in ARID1B are second only to ARID1A in frequency (Fujimoto et al 2012).…”

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confidence: 99%

SWI/SNF regulates a transcriptional program that induces senescence to prevent liver cancer

et al. 2016

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Oncogene-induced senescence (OIS) is a potent tumor suppressor mechanism. To identify senescence regulators relevant to cancer, we screened an shRNA library targeting genes deleted in hepatocellular carcinoma (HCC). Here, we describe how knockdown of the SWI/SNF component ARID1B prevents OIS and cooperates with RAS to induce liver tumors. ARID1B controls p16INK4a and p21 CIP1a transcription but also regulates DNA damage, oxidative stress, and p53 induction, suggesting that SWI/SNF uses additional mechanisms to regulate senescence. To systematically identify SWI/SNF targets regulating senescence, we carried out a focused shRNA screen. We discovered several new senescence regulators, including ENTPD7, an enzyme that hydrolyses nucleotides. ENTPD7 affects oxidative stress, DNA damage, and senescence. Importantly, expression of ENTPD7 or inhibition of nucleotide synthesis in ARID1B-depleted cells results in re-establishment of senescence. Our results identify novel mechanisms by which epigenetic regulators can affect tumor progression and suggest that prosenescence therapies could be employed against SWI/ SNF-mutated cancers.

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ARID1B, a member of the human SWI/SNF chromatin remodeling complex, exhibits tumour-suppressor activities in pancreatic cancer cell lines

Cited by 60 publications

References 37 publications

Insertional Mutagenesis Identifies a STAT3/Arid1b/β-catenin Pathway Driving Neurofibroma Initiation

Insertional Mutagenesis Identifies a STAT3/Arid1b/β-catenin Pathway Driving Neurofibroma Initiation

The ARID1B phenotype: What we have learned so far

SWI/SNF regulates a transcriptional program that induces senescence to prevent liver cancer

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