Oncotarget

Research Papers:

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

Shuiliang Wang, Ling Zhu, Weimin Zuo, Zhiyong Zeng, Lianghu Huang, Fengjin Lin, Rong Lin, Jin Wang, Jun Lu, Qinghua Wang, Lingjing Lin, Huiyue Dong, Weizhen Wu, Kai Zheng, Jinquan Cai, Shunliang Yang, Yujie Ma, Shixin Ye, Wei Liu, Yinghao Yu, Jianming Tan and Bolin Liu _

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Oncotarget. 2016; 7:37693-37713. https://doi.org/10.18632/oncotarget.9264

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Abstract

Shuiliang Wang1, Ling Zhu1, Weimin Zuo1, Zhiyong Zeng2, Lianghu Huang1, Fengjin Lin1, Rong Lin1, Jin Wang1, Jun Lu1, Qinghua Wang1, Lingjing Lin1, Huiyue Dong1, Weizhen Wu1, Kai Zheng1, Jinquan Cai1, Shunliang Yang1, Yujie Ma1, Shixin Ye2, Wei Liu3, Yinghao Yu3, Jianming Tan1, Bolin Liu4

1Fujian Key Laboratory of Transplant Biology, Fuzhou General Hospital, Xiamen University, Fuzhou, Fujian, China

2Department of Thoracic Surgery, Fuzhou General Hospital, Xiamen University, Fuzhou, Fujian, China

3Department of Pathology, Fuzhou General Hospital, Xiamen University, Fuzhou, Fujian, China

4Department of Pathology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

Correspondence to:

Shuiliang Wang, email: [email protected]

Jianming Tan, email: [email protected]

Bolin Liu, email: [email protected]

Keywords: entinostat, Survivin, miRNA, DNMT1, paclitaxel

Received: January 26, 2016     Accepted: April 26, 2016     Published: May 10, 2016

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.


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