title: STAT5 outcompetes STAT3 to regulate the expression of the oncogenic transcriptional modulator BCL6.
abstract: Inappropriate activation of the transcription factors STAT3 and STAT5 has been shown to drive cancer pathogenesis through dysregulation of genes involved in cell survival, growth, and differentiation. Although STAT3 and STAT5 are structurally related, they can have opposite effects on key genes, including BCL6. BCL6, a transcriptional repressor, has been shown to be oncogenic in diffuse large B cell lymphoma. BCL6 also plays an important role in breast cancer pathogenesis, a disease in which STAT3 and STAT5 can be activated individually or concomitantly. To determine the mechanism by which these oncogenic transcription factors regulate BCL6 transcription, we analyzed their effects at the levels of chromatin and gene expression. We found that STAT3 increases expression of BCL6 and enhances recruitment of RNA polymerase II phosphorylated at a site associated with transcriptional initiation. STAT5, in contrast, represses BCL6 expression below basal levels and decreases the association of RNA polymerase II at the gene. Furthermore, the repression mediated by STAT5 is dominant over STAT3-mediated induction. STAT5 exerts this effect by displacing STAT3 from one of the two regulatory regions to which it binds. These findings may underlie the divergent biology of breast cancers containing activated STAT3 alone or in conjunction with activated STAT5.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Walker
authors.forename: Erik A
authors.initials: EA
authors.lastname: Nelson
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Yeh
authors.forename: Luca
authors.initials: L
authors.lastname: Pinello
authors.forename: Guo-Cheng
authors.initials: GC
authors.lastname: Yuan
authors.forename: David A
authors.initials: DA
authors.lastname: Frank
mesh_terms: D000107:Acetylation; D001940:Breast / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000378:metabolism; D006801:Humans; D051560:Proto-Oncogene Proteins c-bcl-6; D012319:RNA Polymerase II / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: C084103:BCL6 protein, human; D004268:DNA-Binding Proteins; D006657:Histones; D051560:Proto-Oncogene Proteins c-bcl-6; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D012319:RNA Polymerase II