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STAT3 Mediates Epigenetic Silencing

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Science's STKE  17 May 2005:
Vol. 2005, Issue 284, pp. tw188
DOI: 10.1126/stke.2842005tw188

Methylation of DNA is a heritable mechanism for silencing gene expression. In some cancers, including certain types of lymphomas, aberrant methylation of the promoters of negative regulators of signaling may contribute to malignancy. Zhang et al. provide evidence that persistent activation of STAT3 (signal transducer and activator of transcription 3) contributes to methylation of the promoter of the gene encoding SHP-1 tyrosine phosphatase, a key negative regulator of T cell signaling. Analysis of the mRNA and protein abundance for DNA methyl transferase 1 (DNMT1), histone deacetylase 1 (HDAC1), and SHP-1 showed an inverse relationship, with SHP-1 low in cells that had high levels of DNMT and HDAC. Furthermore, normal peripheral blood mononuclear cells (PBMC) had low or undetectable amounts of DNMT1 and HDAC1 and no methylation of the SHP-1 promoter, whereas malignant T cells had abundant amounts of these DNA-modifying enzymes and complete or partial methylation of the SHP-1 promoter. The SHP-1 promoter had four potential binding sites for STAT3, and chromatin immunoprecipitation (ChIP) experiments indicated that, in malignant T cells, STAT3, DNMT1, and HDAC1 were bound to the SHP-1 promoter. In cells in which SHP-1 was abundant, little or no binding of these three proteins to the promoter was detectable. Knockdown of DNMT1 or STAT3 with oligonucleotides or silencing RNA (siRNA) led to demethylation of the SHP-1 promoter and the appearance of SHP-1 protein. Thus, STAT3, which is known to be activated in malignant T cells, can promote the epigenetic silencing of SHP-1 through DNA methylation. Why phosphorylated STAT3 is capable of promoting epigenetic silencing of SHP-1 in some cells, but not others, for example mitogen-activated T cells and certain populations of malignant T cells, remains unknown.

Q. Zhang, H. Y. Wang, M. Marzec, P. N. Raghunath, T. Nagasawa, M. A. Wasik, STAT3- and DNA methyltransferase 1-mediated epigenetic silencing of SHP-1 tyrosine phosphatase tumor suppressor gene in malignant T lymphocytes. Proc. Nat. Acad. Sci. U.S.A. 102, 6948-6953 (2005). [Abstract] [Full Text]

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