<i>ARID1A</i> Mutations in Cancer: Another Epigenetic Tumor Suppressor?

Wu, Jiansheng; Roberts, Charles W.M.

doi:10.1158/2159-8290.cd-12-0361

Cited by 385 publications

(337 citation statements)

References 59 publications

(120 reference statements)

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“…Furthermore, in EC, the majority of previous studies have focused on the loss of ARID1A expression as determined by immunohistochemistry or gene sequencing of mutations (7)(8)(9)(10)(11). Therefore, it remains unclear which signaling pathways are influenced by ARID1A mutations and which pathway molecules are targeted by ARID1A mutations in EC pathophysiology.…”

Section: Introductionmentioning

confidence: 99%

Microarray pathway analysis indicated that mitogen-activated protein kinase/extracellular signal-regulated kinase and insulin growth factor 1 signaling pathways were inhibited by small interfering RNA against AT‑rich interactive domain 1A in endometrial cancer

et al. 2017

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Abstract. Mutations in the gene encoding AT-rich interactive domain 1A (ARID1A) are frequently observed in endometrial cancer (EC) but the molecular mechanisms linking the genetic changes remain to be fully understood. The present study aimed to elucidate the influence of ARID1A mutations on signaling pathways. Missense, synonymous and nonsense heterozygous ARID1A mutations in the EC HEC-1-A cell line were verified by Sanger sequencing. Mutated ARID1A small interfering RNA was transfected into HEC-1-A cells. Biochemical microarray analysis revealed 13 upregulated pathways, 17 downregulated pathways, 14 significantly affected disease states and functions, 662 upstream and 512 downstream genes in mutated ARID1A-depleted HEC-1-A cells, among which the mitogen-activated protein kinase/extracellular signal-regulated kinase and insulin-like growth factor-1 (IGF1) signaling pathways were the 2 most downregulated pathways. Furthermore, the forkhead box protein O1 pathway was upregulated, while the IGF1 receptor, insulin receptor substrate 1 and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit b pathways were downregulated. Carcinoma tumorigenesis, tumor cell mitosis and tumor cell death were significantly upregulated disease states and functions, while cell proliferation and tumor growth were significantly downregulated. The results of the present study suggested that ARID1A may be a potential prognostic and therapeutic molecular drug target for the prevention of EC progression.

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Section: Introductionmentioning

confidence: 99%

Microarray pathway analysis indicated that mitogen-activated protein kinase/extracellular signal-regulated kinase and insulin growth factor 1 signaling pathways were inhibited by small interfering RNA against AT‑rich interactive domain 1A in endometrial cancer

et al. 2017

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“…Those complexes are involved in various processes that require alteration of chromatin structure, including DNA repair, DNA synthesis, mitosis and genomic instability. [9][10][11] Most mutations in ARID1A are insertions or deletions, resulting in a truncated protein that is prone to rapid degradation. Therefore, ARID1A gene mutations are highly correlated with loss of protein expression as assessed by immunohistochemistry, even in the absence of mutation in the other allele (eg, haploinsufficiency).…”

mentioning

confidence: 99%

Loss of ARID1A expression and its relationship with PI3K-Akt pathway alterations, TP53 and microsatellite instability in endometrial cancer

et al. 2013

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The switch/sucrose non-fermentable (SWI/SNF) subunit ARID1A (AT-rich interactive domain 1A gene) has been recently postulated as a novel tumor suppressor of gynecologic cancer and one of the driver genes in endometrial carcinogenesis. However, specific relationships with established molecular alterations in endometrioid endometrial cancer (EEC) are currently unknown. We analyzed the expression of ARID1A in 146 endometrial cancers (130 EECs and 16 non-EECs) in relation to alterations in the PI3K-Akt pathway (PTEN expression/KRAS/PIK3CA mutations), TP53 status (TP53 immunohistochemistry) and microsatellite instability. To discriminate between microsatellite instability due to somatic MLH1 promoter hypermethylation or germline mutations in one of the mismatch repair genes (Lynch syndrome), we included a 'Lynch syndrome set'. This set included 21 cases with confirmed germline mutations and 15 cases that were suspected to have a germline mutation. Loss of ARID1A expression was exclusively found in EECs in 31% (40/130) of the EEC cases. No loss of expression of the other subunits of the SWI/SNF complex, SMARCD3 and SMARCB1, was detected. Alterations in the PI3K-Akt pathway were more frequent when ARID1A expression was lost. Loss of ARID1A and mutant-like TP53 expression was nearly mutually exclusive (P ¼ 0.0004). In contrast to Lynch-associated tumors, a strong association between ARID1A loss and sporadic microsatellite instability was found. Only five cases (14%) of the 'Lynch syndrome set' as compared with 24 cases (75%, Po0.0001) of the sporadic microsatellite-unstable tumors showed loss of ARID1A. These observations suggest that ARID1A is a causative gene, instead of a target gene, of microsatellite instability by having a role in epigenetic silencing of the MLH1 gene in endometrial cancer. Keywords: ARID1A; endometrial cancer; Lynch syndrome; microsatellite instability Recent genome-wide sequencing studies have demonstrated that the AT-rich interactive domain 1A (ARID1A) gene is frequently mutated in a wide variety of cancer types 1 including a subset of gynecological cancers. 2 In ovarian cancer, near half of the clear-cell subtype and 30% of the endometrioid subtype showed ARID1A mutations, 3 particularly those that are related to endometriosis. 4,5 In endometrial cancer, mutations in the ARID1A gene have been reported in approximately 30% of both low-and high-grade endometrioid endometrial cancers (EECs) but not in serous endometrial carcinomas. [6][7][8] ARID1A encodes a large nuclear protein involved in chromatin remodeling and interacts with several other proteins, including the core protein

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“…The SWI/SNF complex has multiple activities, including the following: The promotion of binding of transcription factors, coactivators and compressors; mobilization of histone-modifying enzymes; promotion of binding of nucleosomes with promoter and enhancer regions; and promotion of chromatin loop formation to induce interactions of enhancers and promoters ( Fig. 1) (7,21). The SWI/SNF complex and ARID1A also regulate transcription to induce steroid hormones: It has been suggested that ARID1A may be involved in recruiting SWI/SNF to regulate genes through its ability to stimulate steroid hormone receptor-mediated transcriptional activation (22,23).…”

Section: Chromatin Remodeling-associated Gene Mutations and Carcinogementioning

confidence: 99%

Aberrant chromatin remodeling in gynecological cancer (Review)

et al. 2017

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Abstract. Epigenetic regulatory mechanisms are a current focus in studies investigating cancer. Chromatin remodeling alters chromatin structure and regulates gene expression, and aberrant chromatin remodeling is involved in carcinogenesis. AT-rich interactive domain-containing protein 1A (ARID1A) and SWItch/sucrose non-fermentable-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4 are remodeling factors that are mutated in numerous types of cancer. In gynecological cancer, ARID1A mutations have been identified in 46-57% of clear cell carcinoma and 30% of endometrioid carcinoma. Mutations of chromodomain helicase, DNA-binding protein 4 have been detected in 17-21% of endometrial serous cancer, and mutations of ARID1A and mixed-lineage leukemia 3 occur in 36 and 27% of uterine carcinosarcoma, respectively. These data suggest that aberrant chromatin remodeling is a potential cause of cancer, and have led to the development of novel proteins targeting these processes. Additional accumulation of information on the mechanisms of chromatin remodeling and markers for these events may promote personalized anticancer therapies.

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ARID1A Mutations in Cancer: Another Epigenetic Tumor Suppressor?

Cited by 385 publications

References 59 publications

Microarray pathway analysis indicated that mitogen-activated protein kinase/extracellular signal-regulated kinase and insulin growth factor 1 signaling pathways were inhibited by small interfering RNA against AT‑rich interactive domain 1A in endometrial cancer

Microarray pathway analysis indicated that mitogen-activated protein kinase/extracellular signal-regulated kinase and insulin growth factor 1 signaling pathways were inhibited by small interfering RNA against AT‑rich interactive domain 1A in endometrial cancer

Loss of ARID1A expression and its relationship with PI3K-Akt pathway alterations, TP53 and microsatellite instability in endometrial cancer

Aberrant chromatin remodeling in gynecological cancer (Review)

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