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GATA3 recruits UTX for gene transcriptional activation to suppress metastasis of breast cancer.

ABSTRACT: GATA3 has emerged as a prominent transcription factor required for maintaining mammary-gland homeostasis. GATA3 loss is associated with aggressive breast cancer development, but the mechanism by which breast cancer is affected by the loss of GATA3 function remains unclear. Here, we report that GATA3 expression is positively correlated with the expression of UTX, a histone H3K27 demethylase contained in the MLL4 methyltransferase complex, and that GATA3 recruits the chromatin-remodeling MLL4 complex and interacts directly with UTX, ASH2L, and RBBP5. Using RNA sequencing and chromatin immunoprecipitation and sequencing, we demonstrate that the GATA3/UTX complex synergistically regulates a cohort of genes including Dicer and UTX, which are critically involved in the epithelial-to-mesenchymal transition (EMT). Our results further show that the GATA3-UTX-Dicer axis inhibits EMT, invasion, and metastasis of breast cancer cells in vitro and the dissemination of breast cancer in vivo. Our study implicates the GATA3-UTX-Dicer axis in breast cancer metastasis and provides new mechanistic insights into the pathophysiological function of GATA3.

SUBMITTER: Yu W

PROVIDER: S-EPMC6828764 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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GATA3 recruits UTX for gene transcriptional activation to suppress metastasis of breast cancer.

Yu Wenqian W Huang Wei W Yang Yang Y Qiu Rongfang R Zeng Yi Y Hou Yongqiang Y Sun Gancheng G Shi Hang H Leng Shuai S Feng Dandan D Chen Yang Y Wang Shuang S Teng Xu X Yu Hefen H Wang Yan Y

Cell death & disease 20191104 11

GATA3 has emerged as a prominent transcription factor required for maintaining mammary-gland homeostasis. GATA3 loss is associated with aggressive breast cancer development, but the mechanism by which breast cancer is affected by the loss of GATA3 function remains unclear. Here, we report that GATA3 expression is positively correlated with the expression of UTX, a histone H3K27 demethylase contained in the MLL4 methyltransferase complex, and that GATA3 recruits the chromatin-remodeling MLL4 comp ...[more]

PMID: 31685800

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Project description:IntroductionRecent studies have demonstrated that members of the GATA-binding protein (GATA) family (GATA4 and GATA5) might have pivotal roles in the transcriptional upregulation of mucin genes (MUC2, MUC3 and MUC4) in gastrointestinal epithelium. The zinc-finger GATA3 transcription factor has been reported to be involved in the growth control and differentiation of breast epithelial cells. In SAGE (serial analysis of gene expression) studies we observed an intriguing significant correlation between GATA3 and MUC1 mRNA expression in breast carcinomas. We therefore designed the present study to elucidate whether MUC1 expression is regulated by GATA3 in breast cancer cells.MethodsPromoter sequence analysis of the MUC1 gene identified six GATA cis consensus elements in the 5' flanking region (GATA1, GATA3 and four GATA-like sequences). Chromatin immunoprecipitation and electrophoretic mobility-shift assays were employed to study the presence of a functional GATA3-binding site. GATA3 and MUC1 expression was analyzed in vitro with a GATA3 knockdown assay. Furthermore, expression of GATA3 and MUC1 genes was analyzed by real-time RT-PCR and immunohistochemistry on breast cancer-specific tissue microarrays.ResultsWe confirmed the presence of a functional GATA3-binding site on the MUC1 promoter region in the MCF7 cell line. We determined that GATA3 knockdown assays led to a decrease in MUC1 protein expression in MCF7 and T47D cells. In addition, we detected a statistically significant correlation in expression between GATA3 and MUC1 genes at the mRNA and protein levels both in normal breast epithelium and in breast carcinomas (p = 0.01). GATA3 expression was also highly associated with estrogen receptor and progesterone receptor status (p = 0.0001) and tumor grade (p = 0.004) in breast carcinomas.ConclusionOur study provides evidence indicating that GATA3 is probably a mediator for the transcriptional upregulation of MUC1 expression in some breast cancers.

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GATA3 recruits UTX for gene transcriptional activation to suppress metastasis of breast cancer.

Publications

GATA3 recruits UTX for gene transcriptional activation to suppress metastasis of breast cancer.

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