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The AT-rich interactive domain 1A (ARID1A) gene was first discovered as an important subunit of the SWI/SNF (SWI/Sucrose non fermenting, SNF) dye remodeling complex family. The ARID1A gene is a site for frequent mutations in tumors.
ARID1A contains 20 exons encoding a protein consisting of a relative molecular mass of approximately 240 ku and 2 285 amino acid residues, typically located in the nucleus. ARID1A contains two domains, an ARID domain consisting of 100 amino acid residues at the N-terminus and an LXXLL motif enriched with leucine at the C-terminus. Among them, the N-terminal sequence has no specificity, and the three motifs at the C-terminus constitute a glucocorticoid receptor (GR)-binding domain, which can enhance the transcriptional effect by binding to nuclear transcription factors such as GR.
Chromatin remodeling plays an important role in the activities of the nucleus such as transcription, DNA replication and DNA damage repair, highlighting the importance of chromatin remodeling for the regulation of nuclear function. SWI /SNF is an ATP-dependent chromatin remodeling complex. The SWI/SNF chromatin remodeling complex consists of multiple subunits, BRM (Human Brahma) and BRG1 (Brahma-related gene1) are catalytic subunits, both of which are ATPases. They use the energy produced by ATP hydrolysis to provide energy for chromatin remodeling. The macromolecular nuclear protein BAF250a encoded by the ARID1A gene is a member of the SWI/SNF complex. ARID1A regulates the target's three-way orientation through DNA or protein interactions and participates in important nuclear activities such as gene transcription and DNA synthesis. Its dysfunction can cause abnormal chromatin remodeling and cause diseases such as tumors.
Figure 1. ARID1A Domain Structure and Protein Interactions. (Wu, et al. 2013).
ARID1A Is Involved in the Regulation of Cell Proliferation, Differentiation, and Apoptosis
Wu et al. have shown that ARID1A plays an important role in inhibiting cell proliferation, promoting differentiation and apoptosis. ARID1A plays a role in inhibiting cell proliferation by regulating the cell cycle. ARID1A promotes its binding to the cyclin CDK2/CDK4 complex and inhibits its activity by inducing expression of the P21 factor. And the cell cycle is arrested in the G1 phase. In addition to the higher expression in the G0 phase, ARID1A was down-regulated in other phases, and almost completely absent in cells with vigorous cell division.
ARID1A is highly expressed in early embryos and embryonic stem cells by regulating cell differentiation ARID1A. After knocking out the ARID1A gene in embryonic stem cells, embryonic stem cells lose the ability to differentiate into cardiac and adipocytes. ARID1A also plays an important role in early embryonic development. The lack of ARID1A gene causes a change in gene expression profile of embryonic stem cells, increased expression of Gata4, Gata6, Tnt2, and Myl3, and decreased expression of stem cell self-renewing genes, further confirming the importance of ARID1A for stem cell maintenance and differentiation. Samartzis et al. found that the ability of BAF250a-deficient mouse embryonic stem cells to be renewed and differentiated was impaired, and the embryos developed stagnation at 6.5 days. This confirms that ARID1A plays an important role in the differentiation and development of early germ layers. ARID1A also promotes apoptosis by modulating the target genes BCL-2 and cyclin D1.
ARID1A Is Involved in the Regulation of PI3K/AKT Signaling Pathway
The ARID1A mutation has an important correlation with the activation of the PI3K/AKT signaling pathway. PI3CA activating mutations coincide with the ARID1A deletion mutation in ovarian clear cell carcinoma, and PI3CA mutations are present in 46% of ARID1A-deficient tumors. Wiegand et al. found that ARID1A gene mutation in ovarian clear cell carcinoma can activate the PI3K/AKT signaling pathway, causing PIC3CA gene activation and inactivation of the tumor suppressor gene PTEN, leading to tumorigenesis. The PI3K/AKT signaling pathway is frequently mutated in the ARID1A-deficient endometrial carcinoma (deletion of PTEN or activation of PI3CA), and the PI3K/AKT mutation rate is greatly reduced in ARID1A-expressing endometrioid tumors. ARID1A is not only a potential driver of endometrial cancer, but its mutation directly leads to the activation of the PI3K/AKT signaling pathway. Whether ARID1A can be used as a target gene for tumor therapy remains to be further studied.
ARID1A Mutation and Malignant Tumor
Some studies have used somatic sequencing to detect somatic mutations in 110 patients with liver cancer with portal vein thrombosis (PVTTs) and HBV. The mutation of ARID1A gene was the most critical, and the mutation rate of the ARID1A gene was 13% (14/110). It shows that it plays an important role in the occurrence and development of liver cancer. The expression of the macronuclear nucleoprotein BAF250a encoded by the ARID1A gene in 496 breast cancer tissue samples was detected. It was found that 65.3% (324/496) of the BAF250a protein expression was absent. Zhao et al. found that the loss of BAF250a protein expression was closely related to the histological grade of breast cancer, lymph node metastasis, and other clinical case characteristics.
ARID1A plays an important role in tumor suppression in breast cancer, and BAF250a protein may be a new potential target for the treatment of breast cancer. Abnormal chromatin regulation is a key step in the pathogenesis of kidney cancer. Lichner et al. found that the nuclear protein BAF250a encoded by the ARID1A gene was down-regulated in 67% (53/79) clear cell carcinoma samples, and the low expression of ARID1A was associated with tumor stage and differentiation. This suggests that the protein level of ARID1A can be used as a marker to evaluate the prognosis of renal clear cell carcinoma. The ARID1A gene has decreased or absent expression in pancreatic cancer, cholangiocarcinoma, and esophageal cancer. As an important tumor suppressor gene, ARID1A may play an important role in the development of these tumors.