Oncotarget

Research Papers:

HDAC 1/4-mediated silencing of microRNA-200b promotes chemoresistance in human lung adenocarcinoma cells

Dong-Qin Chen, Ban-Zhou Pan, Jia-Yuan Huang, Kai Zhang, Shi-Yun Cui, Wei De, Rui Wang _ and Long-Bang Chen

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Oncotarget. 2014; 5:3333-3349. https://doi.org/10.18632/oncotarget.1948

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Abstract

Dong-Qin Chen1,*, Ban-Zhou Pan1,*, Jia-Yuan Huang1, Kai Zhang1, Shi-Yun Cui1, Wei De2, Rui Wang1 and Long-Bang Chen1

1 Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu 210002, China

2 Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu 210002, China

* Co-first authors

Correspondence:

Rui Wang, email:

Long-Bang Chen, email:

Keywords: lung adenocarcinoma, miR-200b, E2F3, histone deacetylase, chemoresistance

Received: February 15, 2014 Accepted: May 6, 2014 Published: May 7, 2014

Abstract

Chemoresistance is one of the most significant obstacles in lung adenocarcinoma (LAD) treatment, and this process involves genetic and epigenetic dysregulation of chemoresistance-related genes. Previously, we have shown that restoration of microRNA (miR)-200b significantly reverses chemoresistance of human LAD cells by targeting E2F3. However, the molecular mechanisms involved in the silencing of miR-200b are still unclear. Here we showed that histone deacetylase (HDAC) inhibitors could restore the expression of miR-200b and reverse chemoresistant phenotypes of docetaxel-resistant LAD cells. HDAC1/4 repression significantly increased miR-200b expression by upregulating histone-H3 acetylation level at the two miR-200b promoters partially via a Sp1-dependent pathway. Furthermore, silencing of HDAC1/4 suppressed cell proliferation, promoted cell apoptosis, induced G2/M cell cycle arrest and ultimately reversed in vitro and in vivo chemoresistance of docetaxel-resistant LAD cells, at least partially in a miR-200b-dependent manner. HDAC1/4 suppression-induced rescue of miR-200b contributed to downregulation of E2F3, survivin and Aurora-A, and upregulation of cleaved-caspase-3. HDAC1/4 levels in docetaxel-insensitive human LAD tissues, inversely correlated with miR-200b, were upregulated compared with docetaxel-sensitive tissues. Taken together, our findings suggest that the HDAC1/4/Sp1/miR-200b/E2F3 pathway is responsible for chemoresistance of docetaxel-resistant LAD cells.


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