14-3-3σ gene silencing during melanoma progression and its role in cell cycle control and cellular senescence
-
Published:2009-07-30
Issue:1
Volume:8
Page:
-
ISSN:1476-4598
-
Container-title:Molecular Cancer
-
language:en
-
Short-container-title:Mol Cancer
Author:
Schultz Julia,Ibrahim Saleh M,Vera Julio,Kunz Manfred
Abstract
Abstract
Background
The family of 14-3-3 proteins plays an important role in cancer biology by interfering with intracellular signalling pathways and cell cycle checkpoints. The 14-3-3σ isoform acts as a tumor suppressor and is often inactivated during tumor development.
Results
Here, we demonstrate enhanced CpG methylation of the 14-3-3σ gene in lymph node and cutaneous melanoma metastases compared with primary tumors, associated with dramatically reduced mRNA expression. In line with this, treatment of different metastatic melanoma cell lines with 5-aza-2'-deoxycytidine (5-Aza-CdR), a potent inhibitor of cytosine methylation, significantly induces 14-3-3σ protein expression. Additional treatment with histone deacetylase inhibitor 4-phenylbutyric acid (Pba) further enhances 14-3-3σ expression. Induction of 14-3-3σ expression by 5-Aza-CdR/Pba treatment leads to almost complete inhibition of cell proliferation, with cells predominantly arrested in G2-M. The antiproliferative effect of 5-Aza-CdR/Pba was reversed in 14-3-3σ knockdown cells. Similarly, melanoma cell lines stably overexpressing 14-3-3σ show dramatically reduced cell proliferation rates. Moreover, synchronous 14-3-3σ stably overexpressing cells do not progress through cell cycle, but display a permanent increase in the population of 4n DNA containing cells. Interestingly, overexpression of 14-3-3σ induces senescence of melanoma cells and is involved in melanoma cell senescence under genotoxic stress. Finally, 14-3-3σ knockdown supports migratory capacity of melanoma cells in vitro, while 14-3-3σ overexpression has opposing effects.
Conclusion
Taken together, the present report indicates that epigenetic silencing of 14-3-3σ might contribute to tumor progression in malignant melanoma via loss of cell cycle control, impaired cellular senescence program and support of migratory capacity.
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Oncology,Molecular Medicine
Reference42 articles.
1. Miller AJ, Mihm MC: Melanoma. N Engl J Med. 2006, 355: 51-65. 10.1056/NEJMra052166 2. Chudnovsky Y, Khavari PA, Adams AE: Melanoma genetics and the development of rational therapeutics. J Clin Invest. 2005, 115: 813-824. 3. Tucker MA, Goldstein AM: Melanoma etiology: where are we?. Oncogene. 2003, 22: 3042-3052. 10.1038/sj.onc.1206444 4. Chin L: The genetics of malignant melanoma: lessons from mouse and man. Net Rev Cancer. 2003, 3: 559-570. 10.1038/nrc1145. 5. Thomas RK, Baker AC, Debiasi RM, Winckler W, Laframboise T, Lin WM, Wang M, Feng W, Zander T, MacConaill L, Lee JC, Nicoletti R, Hatton C, Goyette M, Girard L, Majmudar K, Ziaugra L, Wong KK, Gabriel S, Beroukhim R, Peyton M, Barretina J, Dutt A, Emery C, Greulich H, Shah K, Sasaki H, Gazdar A, Minna J, Armstrong SA, Mellinghoff IK, Hodi FS, Dranoff G, Mischel PS, Cloughesy TF, Nelson SF, Liau LM, Mertz K, Rubin MA, Moch H, Loda M, Catalona W, Fletcher J, Signoretti S, Kaye F, Anderson KC, Demetri GD, Dummer R, Wagner S, Herlyn M, Sellers WR, Meyerson M, Garraway LA: High-throughput oncogene mutation profiling in human cancer. Nature Genet. 2007, 39: 347-351. 10.1038/ng1975
Cited by
40 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献
|
|