NKAIN2 functions as a novel tumor suppressor in prostate cancer
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Xueying Mao1,*, Fei Luo2,3,*, Lara K. Boyd1,*, Bowei Zhou2,3, Yanling Zhang4,5, Elzbieta Stankiewicz1, Jacek Marzec1, Natasa Vasiljevic6, Yongwei Yu7, Ninghan Feng8, Jia Xu3, Attila Lorincz6, Yong Jiang3, Claude Chelala1, Guoping Ren4, Daniel M Berney1, Shan-Chao Zhao2, Yong-Jie Lu1
1Centre for Molecular Oncology, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK
2Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
3Key Laboratory of Proteomics of Guangdong Province and Key Laboratory of Transcriptomics and Proteomics of Human Diseases Supported by The Ministry of Education of China, Southern Medical University, Guangzhou, 510515, China
4Department of Pathology, The First Affiliated Hospital, Zhejiang University Medical College, Hangzhou, 310009, China
5Department of Gynecology and Obstetrics, Sir Run Run Shaw Hospital, Zhejiang University Medical College, Hangzhou, 310009, China
6Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK
7Department of Pathology, Changhai Hospital, The Second Military Medical University, Shanghai, 200433, China
8Department of Urology, Wuxi Second People’s Hospital, Nanjing Medical University, Wuxi, 214002, China
*These authors contributed equally to this work
Shan-Chao Zhao, email: [email protected]
Yong-Jie Lu, email: [email protected]
Keywords: NKAIN2, tumor suppressor, prostate cancer, chromosomal deletion and truncation, population difference
Received: December 16, 2015 Accepted: August 22, 2016 Published: August 30, 2016
Recurrent chromosome breakpoints at 6q22.31, leading to truncation and potential loss-of-function of the NKAIN2 gene, in Chinese prostate cancer patients were previously identified. In this study we investigated genomic, methylation and expression changes of NKAIN2 in a large number of prostate cancer samples and determined its functional role in prostate cancer cells. Fluorescence in situ hybridization analysis confirmed that NKAIN2 truncation is specific to Chinese while deletion of the gene is frequent in both Chinese and UK prostate cancers. Significantly reduced expression of NKAIN2 was also detected at both RNA and protein levels. Somatic mutations of NKAIN2 in prostate cancer samples exist but at very low frequency, suggesting that it is a putative tumor suppressor gene (TSG) with haploid insufficiency. Our functional studies showed that overexpression of NKAIN2 in prostate cancer cells inhibits cellular growth by promoting cell apoptosis, and decreasing cell migration and invasion. Conversely, knockdown of NKAIN2 promotes prostate cancer cell growth by inhibiting cell apoptosis, and increasing cell migration and invasion. These data imply that NKAIN2 is a novel TSG whose activity is commonly reduced in prostate cancer. It may restrain the disease development and progression by inducing apoptosis and suppressing cancer cell growth, migration and invasion. This study provides new insights into prostate carcinogenesis and opportunities for development of novel therapies for prostate cancer.
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