title: MicroRNA-mediated epigenetic targeting of Survivin significantly enhances the antitumor activity of paclitaxel against non-small cell lung cancer.
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.
authors.affiliation: Fujian Key Laboratory of Transplant Biology, Fuzhou General Hospital, Xiamen University, Fuzhou, Fujian, China.
authors.forename: Shuiliang
authors.initials: S
authors.lastname: Wang
authors.affiliation: Fujian Key Laboratory of Transplant Biology, Fuzhou General Hospital, Xiamen University, Fuzhou, Fujian, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Fujian Key Laboratory of Transplant Biology, Fuzhou General Hospital, Xiamen University, Fuzhou, Fujian, China.
authors.forename: Weimin
authors.initials: W
authors.lastname: Zuo
authors.affiliation: Department of Thoracic Surgery, Fuzhou General Hospital, Xiamen University, Fuzhou, Fujian, China.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Zeng
authors.affiliation: Fujian Key Laboratory of Transplant Biology, Fuzhou General Hospital, Xiamen University, Fuzhou, Fujian, China.
authors.forename: Lianghu
authors.initials: L
authors.lastname: Huang
authors.affiliation: Fujian Key Laboratory of Transplant Biology, Fuzhou General Hospital, Xiamen University, Fuzhou, Fujian, China.
authors.forename: Fengjin
authors.initials: F
authors.lastname: Lin
authors.affiliation: Fujian Key Laboratory of Transplant Biology, Fuzhou General Hospital, Xiamen University, Fuzhou, Fujian, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Lin
authors.affiliation: Fujian Key Laboratory of Transplant Biology, Fuzhou General Hospital, Xiamen University, Fuzhou, Fujian, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Fujian Key Laboratory of Transplant Biology, Fuzhou General Hospital, Xiamen University, Fuzhou, Fujian, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.affiliation: Fujian Key Laboratory of Transplant Biology, Fuzhou General Hospital, Xiamen University, Fuzhou, Fujian, China.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Fujian Key Laboratory of Transplant Biology, Fuzhou General Hospital, Xiamen University, Fuzhou, Fujian, China.
authors.forename: Lingjing
authors.initials: L
authors.lastname: Lin
authors.affiliation: Fujian Key Laboratory of Transplant Biology, Fuzhou General Hospital, Xiamen University, Fuzhou, Fujian, China.
authors.forename: Huiyue
authors.initials: H
authors.lastname: Dong
authors.affiliation: Fujian Key Laboratory of Transplant Biology, Fuzhou General Hospital, Xiamen University, Fuzhou, Fujian, China.
authors.forename: Weizhen
authors.initials: W
authors.lastname: Wu
authors.affiliation: Fujian Key Laboratory of Transplant Biology, Fuzhou General Hospital, Xiamen University, Fuzhou, Fujian, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Zheng
authors.affiliation: Fujian Key Laboratory of Transplant Biology, Fuzhou General Hospital, Xiamen University, Fuzhou, Fujian, China.
authors.forename: Jinquan
authors.initials: J
authors.lastname: Cai
authors.affiliation: Fujian Key Laboratory of Transplant Biology, Fuzhou General Hospital, Xiamen University, Fuzhou, Fujian, China.
authors.forename: Shunliang
authors.initials: S
authors.lastname: Yang
authors.affiliation: Fujian Key Laboratory of Transplant Biology, Fuzhou General Hospital, Xiamen University, Fuzhou, Fujian, China.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Thoracic Surgery, Fuzhou General Hospital, Xiamen University, Fuzhou, Fujian, China.
authors.forename: Shixin
authors.initials: S
authors.lastname: Ye
authors.affiliation: Department of Pathology, Fuzhou General Hospital, Xiamen University, Fuzhou, Fujian, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Pathology, Fuzhou General Hospital, Xiamen University, Fuzhou, Fujian, China.
authors.forename: Yinghao
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Fujian Key Laboratory of Transplant Biology, Fuzhou General Hospital, Xiamen University, Fuzhou, Fujian, China.
authors.forename: Jianming
authors.initials: J
authors.lastname: Tan
authors.affiliation: Department of Pathology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Bolin
authors.initials: B
authors.lastname: Liu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001549:Benzamides / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism*; D049109:Cell Proliferation; D000076123:DNA (Cytosine-5-)-Methyltransferase 1 / Q000378:metabolism; D019175:DNA Methylation; D004357:Drug Synergism; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D035683:MicroRNAs / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011379:Prognosis; D011725:Pyridines / Q000494:pharmacology; D000077022:Survivin
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D001549:Benzamides; D051034:Inhibitor of Apoptosis Proteins; C546703:MIRN203 microRNA, human; C572357:MIRN542 microRNA, human; D035683:MicroRNAs; D011725:Pyridines; D000077022:Survivin; C118739:entinostat; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; C000619380:DNMT1 protein, human; D019869:Phosphatidylinositol 3-Kinases; D017239:Paclitaxel
keywords: DNMT1; Survivin; entinostat; miRNA; paclitaxel