MicroRNA-31 is a transcriptional target of histone deacetylase inhibitors and a regulator of cellular senescence [Gene Regulation]

March 3rd, 2015 by Cho, J.-H., Dimri, M., Dimri, G. P.

MicroRNAs (miRNAs) have emerged as important regulators of tumorigenesis. Several miRNAs, which can function either as oncomiRs or tumor suppressive miRs are deregulated in cancer cells. The microRNA-31 (miR-31) has been shown to be overexpressed in metastatic breast cancer. It promotes multiple oncogenic phenotypes, including proliferation, motility and invasion of cancer cells. Using a breast cancer-related miRNA array analysis, we identified miR-31 as a novel target of histone deacetylase inhibitors (HDACi) in breast cancer cells. Specifically, we show that sodium butyrate (NaB) and Panobinostat (LBH589), two broad-spectrum HDAC inhibitors upregulate hsa-miR-31 (miR-31). The upregulation of miR-31 was accompanied by repression of the polycomb group (PcG) protein BMI1 and induction of cellular senescence. We further show that inhibition of miR-31 overcomes senescence-inducing effect of HDACi, and restores expression of the PcG protein BMI1. Interestingly, BMI1 also acts as a repressor of miR-31 transcription, suggesting a cross-negative feedback loop between the expression of miR-31 and BMI1. Our data suggest that miR-31 is an important physiological target of HDACi, and that it is an important regulator of senescence relevant to cancer. These studies further suggest that manipulation of miR-31 expression can be used to modulate senescence-related pathological conditions such as cancer, and the ageing process.