Dataset Information

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.

SUBMITTER: Takao C

PROVIDER: S-EPMC5264034 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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

Takao Chika C Morikawa Akemi A Ohkubo Hiroshi H Kito Yusuke Y Saigo Chiemi C Sakuratani Takuji T Futamura Manabu M Takeuchi Tamotsu T Yoshida Kazuhiro K

Journal of Cancer 20170101 1

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 ...[more]

PMID: 28123592

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Project description:Wongabel virus (WONV) is an arthropod-borne rhabdovirus that infects birds. It is one of the growing array of rhabdoviruses with complex genomes that encode multiple accessory proteins of unknown function. In addition to the five canonical rhabdovirus structural protein genes (N, P, M, G, and L), the 13.2-kb negative-sense single-stranded RNA (ssRNA) WONV genome contains five uncharacterized accessory genes, one overlapping the N gene (Nx or U4), three located between the P and M genes (U1 to U3), and a fifth one overlapping the G gene (Gx or U5). Here we show that WONV U3 is expressed during infection in insect and mammalian cells and is required for efficient viral replication. A yeast two-hybrid screen against a mosquito cell cDNA library identified that WONV U3 interacts with the 83-amino-acid (aa) C-terminal domain of SNF5, a component of the SWI/SNF chromatin remodeling complex. The interaction was confirmed by affinity chromatography, and nuclear colocalization was established by confocal microscopy. Gene expression studies showed that SNF5 transcripts are upregulated during infection of mosquito cells with WONV, as well as West Nile virus (Flaviviridae) and bovine ephemeral fever virus (Rhabdoviridae), and that SNF5 knockdown results in increased WONV replication. WONV U3 also inhibits SNF5-regulated expression of the cytokine gene CSF1. The data suggest that WONV U3 targets the SWI/SNF complex to block the host response to infection.The rhabdoviruses comprise a large family of RNA viruses infecting plants, vertebrates, and invertebrates. In addition to the major structural proteins (N, P, M, G, and L), many rhabdoviruses encode a diverse array of accessory proteins of largely unknown function. Understanding the role of these proteins may reveal much about host-pathogen interactions in infected cells. Here we examine accessory protein U3 of Wongabel virus, an arthropod-borne rhabdovirus that infects birds. We show that U3 enters the nucleus and interacts with SNF5, a component of the chromatin remodeling complex that is upregulated in response to infection and restricts viral replication. We also show that U3 inhibits SNF5-regulated expression of the cytokine colony-stimulating factor 1 (CSF1), suggesting that it targets the chromatin remodeling complex to block the host response to infection. This study appears to provide the first evidence of a virus targeting SNF5 to inhibit host gene expression.

Dataset Information

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

Publications

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

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