Histone deacetylases mediate the silencing of miR-15a, miR-16, and miR-29b in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) demonstrates a global down-regulation of the microRNAs, miR-15a and miR-16, and a selective silencing of the related microRNA, miR-29b, in aggressive disease. Deletions in chromosome 13 [del(13q14)] partially account for the loss of expression of miR-15a and miR-16, but the mechanisms by which miR-29b becomes silenced is unknown. Here, we show that the histone deacetylases (HDACs) are over-expressed in CLL and mediate the epigenetic silencing of miR-15a, miR-16 and miR-29b. HDAC inhibition triggered the accumulation of the transcriptionally activating chromatin modification, H3K4me2, and restored the expression of miR-15a, miR-16 and miR-29b in approximately 35% of samples. Ectopic expression of miR-15a and miR-16 as well as HDAC inhibition-induced expression of miR-15a, miR-16 or miR-29b in primary CLL cells was associated with declines in the levels of Mcl-1, but not Bcl-2, mitochondrial dysfunction and induction of cell death. Thus, our results identify that HDACs aberrantly silence the expression of the critical tumor suppressor microRNAs, miR-15a, miR-16 and miR-29b in CLL. Deacetylase inhibition may identify a therapeutic strategy that restores the expression of these miRNA to antagonize Mcl-1, an important survival protein in these cells. Consequently, CLL patients that exhibit such epigenetic silencing may benefit from HDAC inhibitor-based therapy. [ABSTRACT FROM AUTHOR]