ARID1A Deficiency Impairs the DNA Damage Checkpoint and Sensitizes Cells to PARP Inhibitors

Shen, Jianfeng; Peng, Yang; Wei, Leizhen; Zhang, Wei; Yang, Lin; Lan, Li; Kapoor, Prabodh; Zhang, Ju; Mo, Qianxing; Shih, Ie Ming; Uray, Iván P.; Wu, Xiangwei; Brown, Powel H.; Shen, Xuetong; Mills, Gordon B.; Peng, Guang

doi:10.1158/2159-8290.cd-14-0849

Cited by 404 publications

(411 citation statements)

References 60 publications

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“…these complexes rearrange the distribution of nucleosomes, thereby modifying chromatin configuration and DNA accessibility to cellular machineries involved in transcription, DNA replication, DNA methylation, and DNA repair (1)(2)(3).…”

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confidence: 99%

Inactivating ARID1A Tumor Suppressor Enhances TERT Transcription and Maintains Telomere Length in Cancer Cells

Rahmanto¹,

Jung²,

et al. 2016

Journal of Biological Chemistry

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ARID1A is a tumor suppressor gene that belongs to the switch/sucrose non-fermentable chromatin remodeling gene family. It is mutated in many types of human cancer with the highest frequency in endometrium-related ovarian and uterine neoplasms including ovarian clear cell, ovarian endometrioid, and uterine endometrioid carcinomas. We have previously reported that mutations in the promoter of human telomerase reverse transcriptase (TERT) rarely co-occur with the loss of ARID1A protein expression, suggesting a potential role of ARID1A in telomere biology. In this study, we demonstrate that ARID1A negatively regulates TERT transcriptional regulation and activity via binding to the regulatory element of TERT and promotes a repressive histone mode. Induction of ARID1A expression was associated with increased occupancy of SIN3A and H3K9me3, known transcription repressor and histone repressor marks, respectively. Thus, loss of ARID1A protein expression caused by inactivating mutations reactivates TERT transcriptional activity and confers a survival advantage of tumor cells by maintaining their telomeres. ARID1A3 encodes BAF250 (also known as p270), which interacts with the ATPase subunit, BRG1 or BRM, and a set of core subunits (BAF47, BAF155, and BAF170) to form the switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex. By utilizing the energy from ATP hydrolysis, these complexes rearrange the distribution of nucleosomes, thereby modifying chromatin configuration and DNA accessibility to cellular machineries involved in transcription, DNA replication, DNA methylation, and DNA repair (1-3).The discovery of molecular genetic aberrations in chromatin remodelers converged genetic and epigenetic dysregulation, which contributes to the development and progression of numerous diseases, including cancer. Somatic ARID1A mutations were first discovered in ovarian clear cell carcinoma (4, 5) and subsequently reported in endometrium-derived carcinomas and several other cancer types (6, 7). Mutations of ARID1A occur throughout the entire coding sequence, mostly frameshift and nonsense mutations, thereby resulting in a loss of ARID1A protein expression. Hence, ARID1A is implicated as a tumor suppressor, and indeed, functional studies have demonstrated that ARID1A loss can promote tumorigenesis by affecting proliferation, differentiation, and apoptosis (8 -10). At the molecular level, our previous study demonstrated that the ARID1A complex interacted and collaborated with p53 to regulate transcription of several effectors including CDKN1A encoding p21 (8). In genetically engineered mice, whereas Arid1a deletion by itself is insufficient to transform cells, codeletion of Arid1a with either Pten or Pik3ca is required to drive the formation of ovarian endometrioid and clear cell-like carcinomas, respectively (11, 12).To further elucidate molecular mechanisms of ARID1A in preventing tumorigenesis, we sought to identify additional molecular genetic alterations that tend to be absent in ARID1A mutated tumors. The nature of ...

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confidence: 99%

Inactivating ARID1A Tumor Suppressor Enhances TERT Transcription and Maintains Telomere Length in Cancer Cells

Rahmanto¹,

Jung²,

et al. 2016

Journal of Biological Chemistry

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“…To gain insight into the mechanisms by which Arid1a loss promotes tumorigenesis in the Chaos3 model, we considered data showing that Arid1a is required for efficient functioning of the DNA damage response (DDR), specifically the G2/M cell-cycle checkpoint that helps suppress genomic instability (GIN) and tumorigenesis (Lobrich and Jeggo 2007;Shen et al 2015) . Since Chaos3 cells have chronic replication stress and GIN (Shima et al 2007;Kawabata et al 2011;Bai et al 2016), it is possible that a loss or reduction of ARID1A in a cell allows escape from DDR-mediated growth arrest or apoptosis, thus promoting carcinogenesis.…”

Section: Resultsmentioning

confidence: 99%

The Chromatin Remodeling ComponentArid1aIs a Suppressor of Spontaneous Mammary Tumors in Mice

Kartha¹,

Shen

Maskin³

et al. 2016

Genetics

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Human cancer genome studies have identified the SWI/SNF chromatin remodeling complex member ARID1A as one of the most frequently altered genes in several tumor types. Its role as an ovarian tumor suppressor has been supported in compound knockout mice. Here, we provide genetic and functional evidence that Arid1a is a bona fide mammary tumor suppressor, using the Chromosome aberrations occurring spontaneously 3 (Chaos3) mouse model of sporadic breast cancer. About 70% of mammary tumors that formed in these mice contained a spontaneous deletion removing all or part of one Arid1a allele. Restoration of Arid1a expression in a Chaos3 mammary tumor line with low Arid1a levels greatly impaired its ability to form tumors following injection into cleared mammary glands, indicating that ARID1A insufficiency is crucial for maintenance of these Trp53-proficient tumors. Transcriptome analysis of tumor cells before and after reintroduction of Arid1a expression revealed alterations in growth signaling and cell-cycle checkpoint pathways, in particular the activation of the TRP53 pathway. Consistent with the latter, Arid1a reexpression in tumor cells led to increased p21 (Cdkn1a) expression and dramatic accumulation of cells in G2 phase of the cell cycle. These results not only provide in vivo evidence for a tumor suppressive and/or maintenance role in breast cancer, but also indicate a potential opportunity for therapeutic intervention in ARID1A-deficient human breast cancer subtypes that retain one intact copy of the gene and also maintain wild-type TRP53 activity.

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“…Some research suggested that ARID1A-mutated cancer may also be treated by targeting residual SWI/SNF activity, the PI3K/AKT pathway, the tumor immunological microenvironment, stabilizing wild-type p53 and by targeting the DNA damage response [47]. Recently it has been found that mutated ARID1A also associated with defects in DNA repair [48]. Such mutations can be another possible target of PARPi to treat cancer.…”

Section: Other Important Genesmentioning

confidence: 99%

BRCA1 and BRCA2 Mutation in Pancreatic Cancer: Significance in Therapeutic Approach

Chakraborty¹

2017

Austin J Gastroenterol

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Germline mutations in the tumour suppressor genes breast cancer antigen gene BRCA1 and BRCA2 have been proven to portend a drastically increased lifetime risk of breast and ovarian cancers in the individuals who carry them. A number of studies have shown that the third most common cancer associated with these mutations is pancreatic cancer. Pancreatic ductal adenocarcinoma (PDAC) remains one of the greatest challenges in oncology. Though it is estimated that about 5 percent of patients with pancreatic cancer are BRCA carriers, this subset of individuals may be more responsive to therapies that damage DNA, such as some chemotherapies, radiation therapy and some targeted therapies. As a result, BRCA carriers with pancreatic cancer may live longer than their counterparts who do not carry the mutation. We study the therapeutic approach and importance of BRCA1/2 mutation in pancreatic cancer.

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ARID1A Deficiency Impairs the DNA Damage Checkpoint and Sensitizes Cells to PARP Inhibitors

Cited by 404 publications

References 60 publications

Inactivating ARID1A Tumor Suppressor Enhances TERT Transcription and Maintains Telomere Length in Cancer Cells

Inactivating ARID1A Tumor Suppressor Enhances TERT Transcription and Maintains Telomere Length in Cancer Cells

The Chromatin Remodeling ComponentArid1aIs a Suppressor of Spontaneous Mammary Tumors in Mice

BRCA1 and BRCA2 Mutation in Pancreatic Cancer: Significance in Therapeutic Approach

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