Abstract
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 up-regulate hsa-miR-31 (miR-31). The up-regulation 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 the 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 aging process.
Highlights
Histone deacetylase inhibitor (HDACi) inhibits expression of polycomb group proteins and can differentially regulate expression of miRNAs
In this study, using a miRNA-PCR array, we determined which of the candidate miRNAs are regulated by histone deacetylase inhibitors (HDACi) in breast cancer cells that may be relevant to cellular senescence, a tumor suppressive phenotype induced by HDACi
Aberrant expression of BMI1 is associated with the bypass of senescence, increased proliferation, and oncogenic phenotypes such as increased migration, invasion, and metastasis of cancer cells [14, 15, 18, 25, 43]
Summary
Histone deacetylase inhibitor (HDACi) inhibits expression of polycomb group proteins and can differentially regulate expression of miRNAs. In addition to p16, BMI1 is known to regulate expression of other cancer and aging relevant genes, such as p57, and genes involved in TGF- signaling, endoplasmic reticulum stress, and WNT pathways [22,23,24,25] Because of their role in promoting various cancers, inhibitors of BMI1 and EZH2 are of clinical importance. In this study, using a miRNA-PCR array, we determined which of the candidate miRNAs are regulated by HDACi in breast cancer cells that may be relevant to cellular senescence, a tumor suppressive phenotype induced by HDACi. We report that miR-31 is a novel target of HDACi in breast cancer cells. We further studied whether miR-31 regulates expression of PcG proteins and cellular senescence, and determined whether HDACi induce senescence via up-regulation of miR-31
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