8 SOCS-3 is frequently silenced by hypermethylation and suppresses cell growth in human lung cancer.pdf

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8 SOCS-3 is frequently silenced by hypermethylation and suppresses cell growth in human lung cancer.pdf

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8 SOCS-3 is frequently silenced by hypermethylation and suppresses cell growth in human lung cancer

SOCS-3 is frequently silenced by hypermethylation and suppresses cell growth in human lung cancer Biao He*, Liang You*, Kazutsugu Uematsu*?, Keling Zang*, Zhidong Xu*, Amie Y. Lee*, Joseph F. Costello?, Frank McCormick*, and David M. Jablons*§ *Thoracic Oncology Laboratory, Department of Surgery, and ?Department of Neurological Surgery, Comprehensive Cancer Center, University of California, San Francisco, CA 94115 Edited by George F. Vande Woude, Van Andel Research Institute, Grand Rapids, MI, and approved September 15, 2003 (received for review May 8, 2003) Lung cancer is the leading cause of cancer death in the world, but the molecular mechanisms for its development have not been well characterized. The suppressors of cytokine signaling (SOCS) are inhibitors of cytokine signaling that function via the Janus kinase (JAK)signal transducers and activators of transcription (STAT) pathway. Eight SOCS proteins with similar structures have been identified so far. SOCS family members, however, have distinct mechanisms of inhibition of JAKSTAT signaling. Abnormalities of the JAKSTAT pathway are associated with cancer. Inhibition of signaling results in growth suppression in various cell types. Recently, the involvement of SOCS-1 in carcinogenesis has been reported. Here, we report identification of frequent hypermethyl- ation in CpG islands of the functional SOCS-3 promoter that correlates with its transcription silencing in cell lines (lung cancer, breast cancer, and mesothelioma) and primary lung cancer tissue samples. Restoration of SOCS-3 in lung cancer cells where SOCS-3 was methylation-silenced resulted in the down-regulation of ac- tive STAT3, induction of apoptosis, and growth suppression. Our results suggest that methylation silencing of SOCS-3 is one of the important mechanisms of constitutive activation of the JAKSTAT pathway in cancer pathogenesis. The data also suggest that SOCS-3 therapy may be useful in the treatment of cancer. The Janus kinase (JAK)sig