Histone Deacetylase Inhibitor Sensitizes ERCC1-High Non-small-Cell Lung Cancer Cells to Cisplatin via Regulating miR-149.

Abstract Resistance to platinum-based chemotherapy becomes a major obstacle in non-small cell lung cancer (NSCLC) treatment. Overexpression of the excision repair cross-complementing 1 (ERCC1) gene is reported to negatively influence the effectiveness of cisplatin-based therapy for NSCLCs. Here, we confirm that high ERCC1 expression correlates with cisplatin resistance in NSCLC cells. Importantly, histone deacetylase inhibitors (HDACi) re-sensitize ERCC1-high NSCLC cells to cisplatin both in vitro and in vivo. Mechanistically, HDACi induces the expression of miR-149 by acetylation and activation of E2F1, which directly targets ERCC1 and inhibits ERCC1 expression. Inhibition of miR-149 reverses the promotion effect of HDACi on cisplatin-induced DNA damage and cell apoptosis in ERCC1-high NSCLC cells. In conclusion, this study reveals a novel mechanism by which HDACi re-sensitizes ERCC1-high NSCLC cells to cisplatin via regulation of E2F1/miR-149/ERCC1 axis, and proposes that combination of HDACi and cisplatin might hold promise to be a more effective therapeutic paradigm for ERCC1-high NSCLCs.