Jumonji/ARID1 B (JARID1B) Protein Promotes Breast Tumor Cell Cycle Progression through Epigenetic Repression of MicroRNA let-7e*

Background: The transcriptional repressor and histone demethylase JARID1B promotes G1 progression and breast tumor cell proliferation. Results: JARID1B regulates cyclin D1 expression and cell cycle progression through epigenetic suppression of the let-7e tumor suppressor microRNA. Conclusion: Epigenetic suppression of let-7e by JARID1B allows G1 progression of breast tumor cells. Significance: The mechanism of JARID1B oncogenic activity involves suppression of a tumor suppressor microRNA. MicroRNAs (miRs) function as tumor suppressors or oncogenes in multiple tumor types. Although miR expression is tightly regulated, the molecular basis of miR regulation is poorly understood. Here, we investigated the influence of the histone demethylase Jumonji/ARID1 B (JARID1B) on miR regulation in breast tumor cells. In MCF-7 cells with stable RNAi-mediated suppression of JARID1B expression we identified altered regulation of multiple miRs including let-7e, a member of the let-7 family of tumor suppressor miRs. Chromatin immunoprecipitation analysis demonstrated JARID1B binding to the let-7e promoter region as well as removal of the of H3K4me3 histone mark associated with active gene expression. These results suggest that JARID1B epigenetically represses let-7e expression. JARID1B stimulates tumor cell proliferation by promoting the G1 to S transition. As predicted, suppression of JARID1B resulted in an accumulation of MCF-7 cells in G1. We confirmed that cyclin D1, which also promotes G1 progression, is a direct target of let-7e, and we show that cyclin D1 expression is suppressed in JARID1B knockdown cells. Cyclin D1 expression and cell cycle progression were restored following inhibition of let-7e, suggesting that JARID1B repression of let-7e contributes to cyclin D1 expression and JARID1B-mediated cell cycle progression. Our results indicate that the JARID1B demethylase contributes to tumor cell proliferation through the epigenetic repression of a tumor suppressor miR.

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