EZH2-mediated Puma gene repression regulates non-small cell lung cancer cell proliferation and cisplatin-induced apoptosis
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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
Yifeng Yang, email: firstname.lastname@example.org
Xinmin Zhou, email: email@example.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
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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