Histone deacetylase inhibition reveals a tumor-suppressive function of MYC-regulated miRNA in breast and lung carcinoma

• Published in: Cell death and differentiation Vol. 23; no. 8; pp. 1312 - 1321
• Main Authors: Adams, C M, Eischen, C M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-08-2016; Nature Publishing Group
• Subjects: 13; 3' Untranslated Regions; 38; 631/67/395; 692/699/67; A549 Cells; Apoptosis; Apoptosis - drug effects; Base Sequence; bcl-X Protein - antagonists & inhibitors; bcl-X Protein - genetics; bcl-X Protein - metabolism; Binding Sites; Biochemistry; Biomedical and Life Sciences; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Biology; Cell Cycle Analysis; Cell death; Cell Line, Tumor; Chromatin Immunoprecipitation; Female; Gene expression; Histone Deacetylase Inhibitors - pharmacology; Humans; Immunology; Life Sciences; Lung cancer; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Lymphoma; MicroRNAs; MicroRNAs - metabolism; Original Paper; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Proto-Oncogene Proteins c-myc - metabolism; RNA polymerase; Sequence Alignment; Stem Cells; Up-Regulation - drug effects; United States > US; Nashville Tennessee
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2016.9

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-X
L
, respectively. MYC was also required for the downregulation of
BCL-2
and
BCL-X
L
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-X
L
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.