ARID1A is a subunit of the BAF chromatin remodelling complex that is frequently mutated in cancer. It is challenging to predict how ARID1A loss impacts cancer therapy response because it participates ...

Resistance to BRAF and MAPK inhibitors is a significant challenge in melanoma treatment, driven by adaptive and acquired mechanisms that allow tumour cells to evade therapy. Here, we examined early si...

Bone metastasis is a lethal consequence of breast cancer. AT-rich interaction domain 1 A gene (ARID1A), a subunit of the switch/sucrose non-fermentable (SWI/SNF) complex, regulates immunosuppressive tumor microenvironment. However, its specific role in bone metastasis remains unclear. Here, we show that female patients with ARID1A‑mutated triple negative breast cancer (TNBC) exhibit a higher bone metastasis incidence. Most ARID1A mutations result in loss of protein expression. ARID1A deficiency upregulates the arginine metabolic pathway, increasing ornithine and spermine levels that promote the expansion of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) within the bone marrow, thereby facilitating bone metastasis. Targeting key enzymes of arginase 2 (ARG2) and ornithine decarboxylase 1 (ODC1) in arginine metabolic pathway effectively reduces bone metastasis in ARID1A-deficient models. Collectively, these findings reveal that ARID1A deficiency promotes bone metastasis by

Signet ring cell carcinoma (SRCC) is a lethal malignancy with distinct histologic features, characterized by accumulated mucins in the cytoplasm which compress nuclei. Gastric SRCC is the most common SRCC whose incidence is increasing in recent years. The molecular mechanisms underlying the histopathology remain poorly understood. Here, we report that AT-rich interactive domain-containing protein 1 A (ARID1A), one of the most frequently mutated genes in gastric SRCC, functions as a bona fide tumor suppressor. Its loss, together with Trp53 and Pten loss, drives SRCC in mice. Mechanistically, Arid1a loss upregulates the expressions of mucins through the competing BRD9-containing ncBAF complex. And mucin secretion is impaired by the downregulation of Scin, a direct target of Arid1a in SRCC. Inhibition of Brd9 ameliorates the malignancy of SRCC. Thus, our study reveals dual roles of ARID1A in both mucin production and secretion, providing new mechanistic insights and potential therape

British Journal of Cancer - Loss of ARID1A accelerates prostate tumourigenesis with a proliferative collagen-poor phenotype through co-operation with AP1 subunit cFos

Oncogene - PPP2R1A mutations cause ATR inhibitor sensitivity in ovarian clear cell carcinoma

The ARID1A subunit of the BAF chromatin remodeling complex is frequently mutated in cancer. Simões-Sousa et al. demonstrate that ARID1A promotes the assembly of repair factors on chromatin and promotes cellular survival following exposure to G quadruplex ligands, which hold promise for cancer treatment.

The SWI/SNF chromatin remodelling complex controls proliferation and cell fate determination by regulating chromatin accessibility at promoters and enhancers, thereby modulating programs of gene expression, and has roles in DNA damage response, replication, splicing, and translation, and cell plasticity. The cBAF-exclusive subunit ARID1A acts as scaffold for the assembly of cBAF SWI/SNF complexes through its C-terminal globular domain and is the most frequently mutated SWI/SNF subunit in cancer. More than half of the ARID1A protein sequence contains regions of intrinsic disorder which are important for protein interactions, often mediated by short linear motifs. However, these interactions are notoriously difficult to study. Whilst hundreds of ARID1A interactions have been reported in the literature, their molecular basis remains obscure, and only a few have been explored functionally or mapped at an interface level. Here, we use a PRotein Interaction Screen on a peptide MAtrix (PRISMA) combined with quantitative mass spectrometry to identify novel ARID1A interactions and map amino acid residues and motifs that mediate interactions at high sequence resolution. The ARID1A PRISMA assay recapitulates binding of BAF subunits to ARID1A and detects the previously described binding of YAP1 transcriptional coactivator to a PPXY motif. Our PRISMA data reveals binding sites for transcriptional repressor SIN3A and identifies TOX4, CDK2 and CCNA2 as novel interactors. Mutation of a cell cycle-dependent CDK2 phosphorylation site in ARID1A leads to altered gene expression of microtubule factors and defects in cell proliferation. Our work underscores the utility of PRISMA to uncover weak or low abundance interactions that are not detectable by traditional affinity purification strategies. Together, our results characterise novel interactors and a new mode of regulation of ARID1A, and provide a useful resource to further explore mechanistic aspects of ARID1A function.

AbstractSTUDY QUESTION. Is there an association between the somatic loss of PTEN (phosphatase and tensin homolog) and ARID1A (AT-rich interaction domain 1A

The cell death receptor FAS and its ligand (FASLG) play crucial roles in the selection of B cells du

ARID1A loss in tumor cells triggers anti-tumor immunity via R-loop-derived cytosolic DNA and activation of the STING-type I interferon pathway, defining a molecular mechanism underlying ARID1A mutant anti-tumor immunity and immunotherapy response observed clinically.