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Oncotarget. 2016 Jun 21;7(25):37693-37713. doi: 10.18632/oncotarget.9264.

MicroRNA-mediated epigenetic targeting of Survivin significantly enhances the antitumor activity of paclitaxel against non-small cell lung cancer.

Author information

1
Fujian Key Laboratory of Transplant Biology, Fuzhou General Hospital, Xiamen University, Fuzhou, Fujian, China.
2
Department of Thoracic Surgery, Fuzhou General Hospital, Xiamen University, Fuzhou, Fujian, China.
3
Department of Pathology, Fuzhou General Hospital, Xiamen University, Fuzhou, Fujian, China.
4
Department of Pathology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

Abstract

Elevated expression of Survivin correlates with poor prognosis, tumor recurrence, and drug resistance in various human cancers, including non-small cell lung cancer (NSCLC). The underlying mechanism of Survivin upregulation in cancer cells remains elusive. To date, no Survivin-targeted therapy has been approved for cancer treatment. Here, we explored the molecular basis resulting in Survivin overexpression in NSCLC and investigated the antitumor activity of the class I HDAC inhibitor entinostat in combination with paclitaxel. Our data showed that entinostat significantly enhanced paclitaxel-mediated anti-proliferative/anti-survival effects on NSCLC cells in vitro and in vivo. Mechanistically, entinostat selectively decreased expression of Survivin via induction of miR-203 (in vitro and in vivo) and miR-542-3p (in vitro). Moreover, analysis of NSCLC patient samples revealed that the expression levels of miR-203 were downregulated due to promoter hypermethylation in 45% of NSCLC tumors. In contrast, increased expression of both DNA methytransferase I (DNMT1) and Survivin was observed and significantly correlated with the reduced miR-203 in NSCLC. Collectively, these data shed new lights on the molecular mechanism of Survivin upregulation in NSCLC. Our findings also support that the combinatorial treatments of entinostat and paclitaxel will likely exhibit survival benefit in the NSCLC patients with overexpression of DNMT1 and/or Survivin. The DNMT1-miR-203-Survivin signaling axis may provide a new avenue for the development of novel epigenetic approaches to enhance the chemotherapeutic efficacy against NSCLC.

KEYWORDS:

DNMT1; Survivin; entinostat; miRNA; paclitaxel

PMID:
27177222
PMCID:
PMC5122342
DOI:
10.18632/oncotarget.9264
[Indexed for MEDLINE]
Free PMC Article

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