Histone deacetylases inhibitor trichostatin A increases the expression of Dleu2/miR-15a/16-1 via HDAC3 in non-small cell lung cancer

Abstract

Histone deacetylases (HDACs) inhibitor is a promising new approach to the treatment of lung cancer therapy via inhibiting cell growth and inducing apoptosis. miR-15a and miR-16-1 are important tumor suppressors through modulating B cell lymphoma 2 (Bcl-2), Cyclin D1, D2, and others. However, whether HDACs inhibitor modulates the expression of miR-15a/16-1 in lung cancer is still unknown. The purpose of our study was to identify a new miRNA-mediated mechanism which plays an important role in the anti-cancer effects of HDACs inhibitor. We found HDACs inhibitors trichostatin A (TSA) and sodium butyrate upregulated the expression of miR-15a/16-1, residing in the host tumor suppressor Dleu2 gene, through increasing the histone acetylation in the region of Dleu2/miR-15a/16-1 promoter in lung cancer cells. Moreover, among class Ι HDACs subtypes, only knockdown of HDAC3 by specific siRNA increased the hyperacetylation of Dleu2/miR-15a/16-1 promoter region and finally resulted in the upregulation of miR-15a/16-1. Furthermore, overexpression of miR-15a/16-1, which were always deleted or downregulated in lung cancer cells, effectively suppressed cell growth and reduced colony formation. Finally, TSA reduced the expression of Bcl-2, an important survival protein in lung cancer cells, partly through upregulation of miR-15a/16-1. Therefore, this offers a therapeutic strategy that lung cancer patients who exhibit low level of miR-15a/16-1 or high activity of HDACs may benefit from HDACs inhibitor-based therapy.

MiR‐16‐5p is frequently down‐regulated in astrocytic gliomas and modulates glioma cell proliferation, apoptosis and response to cytotoxic therapy

“…Previous studies in non‐Hodgkin B‐cell lymphomas and non‐small cell lung cancers reported that MYC and HDAC3 colocalize to the promoters of the miR‐15a/miR‐16‐1 cluster host gene DLEU2 , and that inhibition of HDAC3 increases histone acetylation of these promoters . To investigate whether a similar mechanism operates in glioma cells, we performed knock‐down experiments of HDAC3 in the glioma cell lines T98G and U251MG.…”

“…Involvement of DNA methylation and histone modifications have been implicated in the regulation of miR‐16‐5p in CLL and non‐small cell lung cancer . Therefore, we investigated whether treatment of A172, T98G, TP365MG and U138MG glioma cells with the histone deacetylase inhibitor TSA had an impact on miR‐16‐5p expression.…”

“…We also investigated potential mechanisms causing miR‐16‐5p down‐regulation in gliomas. Studies on haematopoietic neoplasms showed that miR‐16 ‐ 5p expression may not only be reduced by copy number losses but also by epigenetic mechanisms, in particular histone modifications . In B‐cell lymphoma and lung carcinoma, transcription of DLEU2 and the miR‐ 15a/miR‐16‐1 locus may be repressed by binding of MYC to DLEU2 promoter regions, followed by recruitment of HDAC3 .…”

MicroRNA-124 Controls the Proliferative, Migratory, and Inflammatory Phenotype of Pulmonary Vascular Fibroblasts

“…42 Reports in cancer have also suggested that epigenetic modulation of mRNA expression by HDAC inhibitors could be an important adjunctive treatment approach in cancer chemotherapy. 71 …”

Transcriptional Repression of Histone Deacetylase 3 by the Histone Demethylase KDM2A Is Coupled to Tumorigenicity of Lung Cancer Cells

“…Recently, Chen et al (43) reported that the HDAC inhibitor trichostatin A may increase the expression of the potential tumor suppressor cluster Dleu2/miR-15a/16-1 via HDAC3 inhibition in two NSCLC cell lines, A549 and H1299. In contrast, our results suggest that HDAC3 is involved in tumor suppression in the NSCLC cell lines H1975 and H1792.…”