Hdac Inhibition Unmasks A Microrna-Mediated Mechanism Of Tumor Suppression

Genetic lesions resulting in epigenetic dysregulation have a newly appreciated role in tumor initiation and progression. Alterations in epigenetic enzymes, such as histone deacetylases (HDACs), lead to dynamic changes in the epigenetic landscape that are postulated to alter the expression of critical mediators of tumorigenesis. HDACs not only alter the expression of protein-coding genes, but also affect noncoding RNAs, including microRNA (miRNA). Recent evidence suggests that miRNA are one of the largest classes of regulatory molecules and, given their broad impact on gene expression, it is not surprising they have a significant role in tumorigenesis. Although, small molecule inhibitors of HDACs have demonstrated therapeutic utility, the molecular events underlying the observed selective killing of cancer cells are incompletely resolved. We determined that HDAC inhibition in numerous hematopoietic malignancies relieved the Myc-mediated transcriptional repression of miRNA with known tumor suppressive properties, namely the miR-15 and let-7 families. Specifically, following HDAC inhibition, Myc, which normally represses the miR-15 and let-7 families in cancer cells, transcriptionally activated their expression. In addition, we demonstrated that Myc was required for this HDAC inhibition-induced miRNA upregulation. As a result, transcript levels of the miR-15 and let-7 families increased, which subsequently targeted and decreased the expression of anti-apoptotic Bcl-2 and Bcl-x L , respectively, inducing apoptosis in multiple hematopoietic malignancies. Unexpectedly, we demonstrated that, in normal cells, dysregulated Myc transcriptionally upregulated these miRNA as a means to prevent cellular transformation, revealing a novel mechanism whereby Myc induces apoptosis independent of the p53 tumor suppressor. Our results expose a previously unknown, and surprisingly general, mechanism of Myc-induced apoptosis that capitalizes on miRNA. Importantly, our data provide insight into the molecular underpinnings following HDAC inhibition and contribute new knowledge that should aid in the development of improved cancer therapeutics. Citation Format: Clare M. Adams, Scott W. Hiebert, Christine M. Eischen. HDAC inhibition unmasks a microRNA-mediated mechanism of tumor suppression. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr A24.