Abstract
Histone deacetylase (HDAC) inhibition leads to dynamic changes in the epigenetic landscape that is postulated to alter the expression of critical mediators of cellular proliferation and death. While current HDAC inhibitors have shown to be efficacious in the treatment of specific hematologic malignancies, their therapeutic utility in epithelial-based cancers warrants further evaluation. Moreover, the mechanisms of HDAC inhibition-induced cancer cell death are not completely understood. Therefore, elucidation of the underlying pathways engaged by HDAC inhibition may enable the development of more effective therapeutic strategies. Here, we report that HDAC inhibition in human breast and lung carcinoma cells activates an apoptotic mechanism mediated by microRNA (miRNA) and induced by the oncogene MYC. Specifically, following HDAC inhibition, MYC, which normally represses miR-15 and let-7 families, transcriptionally activated their expression and MYC was required for this miRNA upregulation. As a result, transcript levels of the tumor-suppressive miR-15 and let-7 families increased, which targeted and decreased the expression of the crucial prosurvival genes BCL-2 and BCL-XL, respectively. MYC was also required for the downregulation of BCL-2 and BCL-XL following HDAC inhibition. Blocking the binding sites of the miR-15 and let-7 families in the 3'-untranslated regions of BCL-2 and BCL-XL protected against HDAC inhibition-induced apoptosis. These results provide important insight into the molecular underpinnings of HDAC inhibition-induced cell death in breast and lung cancer and reveal a tumor-suppressive role for MYC-regulated miRNA that is activated with HDAC inhibition.