MicroRNA-31 is a transcriptional target of histone deacetylase inhibitors and a regulator of cellular senescence.
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.
From the Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, D. C.
Joon-Ho
JH
Cho
From the Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, D. C. mdimri@gwu.edu.
Manjari
M
Dimri
From the Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, D. C. gdimri@gwu.edu.
Goberdhan P
GP
Dimri
D017209:Apoptosis; D020148:Butyric Acid / Q000494:pharmacology*; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics*; D025461:Feedback, Physiological; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D061986:MCF-7 Cells; D035683:MicroRNAs / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D046228:Microarray Analysis; D020411:Oligonucleotide Array Sequence Analysis; D000077767:Panobinostat; D063150:Polycomb Repressive Complex 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic
C069077:BMI1 protein, human; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; C534612:MIRN31 microRNA, human; D035683:MicroRNAs; D020148:Butyric Acid; D000077767:Panobinostat; D063150:Polycomb Repressive Complex 1
Breast Cancer; Histone Deacetylase Inhibitor (HDAC Inhibitor) (HDI); MicroRNA (miRNA); Polycomb; Senescence; bmi1