title: REST negatively and ISGF3 positively regulate the human STAT1 gene in melanoma.
abstract: STAT1 plays a pivotal role in signal transduction and transcriptional activation in response to type I and II IFNs. Regulation of STAT1 expression has significant consequences in human cancer cells, where STAT1 deficiencies have been associated with cellular resistance to type I IFN. Distinct promoter, enhancer, and repressor regions have previously been described in the regulatory part of the human STAT1 gene extending as far as the second intron. A putative IFN-stimulated response element sequence in the STAT1 promoter is inducible by type I IFN and binds the IFN-α/β-induced complex, ISGF3. Together with the previously characterized IRF-E/GAS/IRF-E (IGI) motif, these positive regulatory elements provide a means for intracellular amplification of STAT1 expression, which is necessary for increasing cell responsiveness to the IFNs. In contrast, the transcriptional repressor REST binds to an RE-1 element in the STAT1 repressor region and in doing so represses transcription from the STAT1 gene regulatory region in melanoma cells lines. Repression significantly decreased in a REST-null cell line. Altering REST function from a transcriptional repressor into an activator as REST-VP16 increased expression from RE-1-targeted reporters. RNA expression of 65 melanoma cell lines by microarray and selected lines with known IFN responsiveness showed significant inverse correlations between STAT1/REST that were related to cellular responses to IFN. Thus REST, through the intronic RE-1 element, provides a means for downregulating STAT1 expression, affecting melanoma responsiveness to IFN. Intracellular levels of REST may be a useful marker to test for IFN resistance and as a novel therapeutic target in IFN-resistant melanomas.
authors.affiliation: School of Medical Science and Genomics Research Centre, Griffith Health Institute, Griffith University, Gold Coast Campus, Australia.
authors.forename: James
authors.initials: J
authors.lastname: Amalraj
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Cutler
authors.forename: Ibtisam
authors.initials: I
authors.lastname: Ghazawi
authors.forename: Glen M
authors.initials: GM
authors.lastname: Boyle
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Ralph
mesh_terms: D000818:Animals; D047369:Chromatin Immunoprecipitation; D015870:Gene Expression; D006801:Humans; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit / Q000235:genetics / Q000378:metabolism*; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051381:Rats; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation; D014162:Transfection; D000099229:RE1-Silencing Transcription Factor
chemical_list: D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D000099229:RE1-Silencing Transcription Factor; C494227:IRF9 protein, human; C494079:STAT1 protein, human