MS‐275 potentiates the effect of YM‐155 in lung adenocarcinoma via survivin downregulation induced by miR‐138 and miR‐195

Abstract

Background YM‐155 has been proven to be an efficient antitumor suppressor in non‐small cell lung cancer (NSCLC) cells. However, the suppressive effect of YM‐155 on the expression of survivin is not sufficient and has a short half‐life. MS‐275, a histone deacetylase inhibitor, has significant antitumor capacity with a relatively long half‐life. Our study explored whether MS‐275 could enhance the inhibitory effect of YM‐155 on LUAD proliferation. Methods To investigate the synergistic effect of MS‐275 and YM‐155, we employed methyl thiazolyl tetrazolium and colony formation assays to access the inhibition effect of MS‐275, YM‐155, or a combination in A549 and HCC827 cell lines. We then detected the effect of MS‐275 and YM‐155 on the expression of survivin and pro‐apoptotic proteins by Western blot and miR‐138 or miR‐195 expression by quantitative PCR. We also analyzed the methylation level of microRNAs (miRNAs) using methylation‐sensitive quantitative PCR. Finally, we investigated the interaction between miRNAs and survivin by luciferase reporter assay. Results MS‐275 facilitated an inhibitory effect of YM‐155 on lung adenocarcinoma cell proliferation. MS‐275 can upregulate the level of acetylated H3, promote the degradation of DNA methyltransferases, and inhibit the methylation of miR‐138 and miR‐195 genes to elevate the expression of miR‐138 and miR‐195. Moreover, miR‐138 and miR‐195 showed a synergistic effect with YM‐155 by directly binding to the 3 untranslated region of survivin to attenuate its expression. Conclusion For the first time, we report the synergistic effective of MS‐275 and YM‐155 and suggest a new direction for the future application of YM‐155.

Keywords

• LUAD
• MS‐275
• NSCLC
• survivin
• YM‐155