Advance Publications: Research Papers:
Ski is silenced by methylation and acts as tumor suppressor in nonsmall cell lung cancer
Mian Xie1, Xiaojun Wu2, Chaosheng He3, Jiexia Zhang1, Jinjun Zhang4
1China State Key Laboratory of Respiratory Disease and Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
2State Key Laboratory of Oncology in Southern China, Department of Colorectal Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, China
3Department of Internal Medicine, Guangdong General Hospital, Guangzhou, China
4Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
Correspondence to:
Mian Xie, e-mail: [email protected]
Keywords: lung cancer, Ski, DNA methylation, prognosis
Received: July 20, 2015 Accepted: November 22, 2015 Published: December 12, 2015
ABSTRACT
Epigenetic silencing of tumor suppressors contributes to the development and progression of lung cancer. We recently found that Ski was hypermethylated in lung cancer. This study aimed to clarify its epigenetic alteration, molecular mechanisms and clinical significance in lung cancer. Ski methylation was evaluated by methylation-specific PCR (MS-PCR) and bisulfite sequencing. mRNA level of Ski was measured by RT-PCR and compared with the methylation status. Ski methylation correlated with decreased mRNA expression in human lung cancer cell lines. Ski hypermethylation was detected in 56.0% of primary lung tumors and associated with poor differentiation and late tumor stage. Demethylation agent 5-aza-2′-deoxycytidine (5-aza-2′dC) restored Ski expression. Re-expression of Ski in lung cancer cells inhibited cell proliferation, clonogenicity, migration, invasion and tumor formation. Ski decreased transcriptional activities of Smads and TAZ. Multivariate analysis showed that patients with Ski positive expression had a better overall survival in resected non-small cell lung cancer (NSCLC) patients. Our results revealed that Ski acts as a tumor suppressor inactivated by DNA methylation and is an independent prognostic factor of lung cancer.