Downregulation of ARID1A, a component of the SWI/SNF chromatin remodeling complex, in breast cancer

Abstract

Recent studies unraveled that AT-rich interactive domain-containing protein 1A (ARID1A), a subunit of the mammary SWI/SNF chromatin remodeling complex, acts as a tumor suppressor in various cancers. In this study, we first evaluated ARID1A expression by immunohistochemistry in invasive breast cancer tissue specimens and assessed the correlation with the prognosis of patients with breast cancer. Non-tumorous mammary duct epithelial cells exhibited strong nuclear ARID1A staining, whereas different degrees of loss in ARID1A immunoreactivity were observed in many invasive breast cancer cells. We scored ARID1A immunoreactivity based on the sum of the percentage score in invasive cancer cells (on a scale of 0 to 5) and the intensity score (on a scale of 0 to 3), for a possible total score of 0 to 8. Interestingly, partial loss of ARID1A expression, score 2 to 3, was significantly correlated with poor disease free survival of the patients. Subsequently, we performed siRNA-mediated ARID1A knockdown in cultured breast cancer cells followed by comprehensive gene profiling and quantitative RT-PCR. Interestingly, many genes were downregulated by partial loss of ARID1A, whereas RAB11FIP1 gene expression was significantly upregulated by partial loss of ARID1A expression in breast cancer cells. In contrast, a more than 50% reduction in ARID1A mRNA decreased RAB11FIP1gene expression. Immunoblotting also demonstrated that partial downregulation of ARID1A mRNA at approximately 20% reduction significantly increased the expression of RAB11FIP1 protein in MCF-7 cells, whereas, over 50% reduction of ARID1A mRNA resulted in reduction of RAB11FIP1 protein in cultured breast cancer cells. Recent studies reveal that RAB11FIP1 overexpression leads to breast cancer progression. Altogether, the present findings indicated that partial loss of ARID1A expression is linked to unfavorable outcome for patients with breast cancer, possibly due to increased RAB11FIP1 expression.

ARID1A knockdown triggers epithelial‐mesenchymal transition and carcinogenesis features of renal cells: role in renal cell carcinoma

“…4) and invasive capability (Fig. 5 E, F ), consistent with the data reported in liver, breast, and gastric cancers, in which loss of ARID1A promoted cell invasion (45–47). The siARID1A‐transfected MDCK cells also exhibited enlargement of nuclei and multicellular spheroids (Fig.…”

BRG1 Activates Proliferation and Transcription of Cell Cycle-Dependent Genes in Breast Cancer Cells

“…The SWI/SNF chromatin remodeling complex has attracted increasing attention, particularly in cancer biology due to mutations, deletions and insertions in BRG1, and in some of the SWI/SNF core subunits (e.g., SNF5, ARID1A) in~20% of human tumors. Mutations associated with gain and loss of function, as well as fluctuation in the expression of SWI/SNF components, are linked to the occurrence of cancer and its progression in several ways [15,16]. BRG1 was initially considered as a tumor suppressor, based on, for example, premises from mouse model of primary cells, where inactivation of Brg1 and Snf5 leads to an overall decrease in nucleosome occupancy at a large number of promoters, products of which potentiate cell proliferation [17].…”

ARID1A‐SIN3A drives retinoic acid‐induced neuroblastoma differentiation by transcriptional repression of TERT

“…A variety of loss‐ or gain‐of‐function mutations in SWI/SNF subunit genes have been reported to impact on a number of cancers in a highly specific tumor‐ and tissue‐dependent manner . Inactivated SWI/SNF mutation or loss of the AT‐rich interaction domain 1A (ARID1A) subunit is frequently observed in various solid tumors including NB . Emerging data demonstrate that ARID1A interacts with the TERT promoter region to cause chromatin remodeling and potentially recruit transcriptional regulators such as the glucocorticoid receptor (GR), histone deacetylase 6 (HDAC6), and SIN3 transcription regulator family member A (SIN3A) …”

“…12 Inactivated SWI/SNF mutation or loss of the AT-rich interaction domain 1A (ARID1A) subunit is frequently observed in various solid tumors including NB. [13][14][15] Emerging data demonstrate that ARID1A interacts with the TERT promoter region to cause chromatin remodeling 16,17 and potentially recruit transcriptional regulators such as the glucocorticoid receptor (GR), 18 histone deacetylase 6 (HDAC6), 19 and SIN3 transcription regulator family member A (SIN3A). 20 In this study, we demonstrate an inverse association between ARID1A and TERT in cell lines and NB patient cohorts.…”