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Transcription Repressor Activity of Spleen Tyrosine Kinase Mediates Breast Tumor Suppression

¹ Department of Molecular Pathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas; ² Department of Gastrointestinal Surgery, 1st Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; and ³ Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland

Requests for reprints: Jiale Dai, Department of Molecular Pathology, University of Texas M.D. Anderson Cancer Center, Box 89, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-8995; Fax: 713-792-4324; E-mail: jldai{at}mdanderson.org.

Spleen tyrosine kinase (SYK) is a candidate tumor suppressor gene in breast. Loss of SYK expression in breast tumors as a result of DNA hypermethylation promotes tumor cell proliferation and invasion and predicts shorter survival of breast cancer patients. We previously reported that, in addition to its well-known cytoplasmic localization, the full-length Syk is also present in the nucleus and that Syk nuclear translocation is a rate-limiting step to determine Syk tumor suppressor function. Here, we show that the full-length form of Syk acts as a transcription repressor in the cell nucleus. Ectopic expression of Syk down-regulates the transcription of FRA1 and cyclin D1 oncogenes. This transcription-repressing activity of Syk is associated with its binding to members of the histone deacetylase family. Syk interacts with transcription factor Sp1 at the Sp1 DNA-binding site in the FRA1 promoter to repress Sp1-activated FRA1 transcription. Thus, breast tumorigenesis and progression resulting from the loss of SYK are underscored by the derepression of Sp1-mediated oncogene transcription.

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