Oncotarget

Research Papers:

EZH2-mediated Puma gene repression regulates non-small cell lung cancer cell proliferation and cisplatin-induced apoptosis

Haidan Liu, Wei Li, Xinfang Yu, Feng Gao, Zhi Duan, Xiaolong Ma, Shiming Tan, Yunchang Yuan, Lijun Liu, Jian Wang, Xinmin Zhou and Yifeng Yang _

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Oncotarget. 2016; 7:56338-56354. https://doi.org/10.18632/oncotarget.10841

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Abstract

Haidan Liu1,2,*, Wei Li4,*, Xinfang Yu5, Feng Gao6, Zhi Duan8, Xiaolong Ma2, Shiming Tan7, Yunchang Yuan3, Lijun Liu1, Jian Wang1, Xinmin Zhou2, Yifeng Yang1,2

1Clinical Center for Gene Diagnosis and Therapy, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China

2Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China

3Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China

4Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China

5Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China

6Department of Ultrasonography, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China

7Department of Hemopathology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China

8Albert Einstein College of Medicine, Bronx, NY, USA

*These authors contributed equally to this work

Correspondence to:

Yifeng Yang, email: yyf627@163.com

Xinmin Zhou, email: mark037100@163.com

Keywords: polycomb repressive complex 2, EZH2, PUMA, non-small cell lung cancer, cisplatin

Received: March 21, 2016     Accepted: July 09, 2016     Published: July 26, 2016

ABSTRACT

Polycomb group (PcG) proteins are highly conserved epigenetic effectors that maintain the silenced state of genes. EZH2 is the catalytic core and one of the most important components of the polycomb repressive complex 2 (PRC2). In non-small cell lung cancer (NSCLC) cells and primary lung tumors, we found that PRC2 components, including EZH2, are overexpressed. High levels of EZH2 protein were associated with worse overall survival rate in NSCLC patients. RNA interference mediated attenuation of EZH2 expression blunted the malignant phenotype in this setting, exerting inhibitory effects on cell proliferation, anchorage-independent growth, and tumor development in a xenograft mouse model. Unexpectedly, we discovered that, in the suppression of EZH2, p53 upregulated modulator of apoptosis (PUMA) expression was concomitantly induced. This is achieved through EZH2 directly binds to the Puma promoter thus epigenetic repression of PUMA expression. Furthermore, cisplatin-induced apoptosis of EZH2-knocking down NSCLC cells was elevated as a consequence of increased PUMA expression. Our work reveals a novel epigenetic regulatory mechanism controlling PUMA expression and suggests that EZH2 offers a candidate molecular target for NSCLC therapy and EZH2-regulated PUMA induction would synergistically increase the sensitivity to platinum agents in non-small cell lung cancers.


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