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.

Circadian disruption-induced microRNAome deregulation in rat mammary gland tissues

“…Together with previous literature that has shown that CD results in increased miRNA promoter methylation, this indicates that the aberrant NF-κB activity and STAT3 levels could potentially be a consequence of miR-146b promoter methylation due to increased levels of DNMT1 [18, 54]. Furthermore, the STAT3 protein has also been shown to induce BCL6 expression by binding to one of two regulatory regions within the BCL6 gene [55]. As a result, the CD-induced increases in STAT3 expression through NF-κB activity may not only cause oncogenic effects on their own, but also contribute to the increase in BCL6 levels.…”

All-trans retinoic acid synergizes with FLT3 inhibition to eliminate FLT3/ITD+ leukemia stem cells in vitro and in vivo

“…38 Phosphorylation of STAT5, a key downstream signaling target of FLT3/ ITD, is strongly inhibited by treatment with FLT3 TKIs such as sorafenib ( Figure 3F). This would have the effect of relieving repression by STAT5 and leading to the observed increased Bcl6 expression.…”

Mechanisms of Jak/STAT Signaling in Immunity and Disease

“…A singular consensus motif has also led to the idea that STATs may antagonize one another by competing for access to the same genomic locales. This concept has been validated for STAT3 and STAT5 - first in T cells, where STAT3-driven IL-17 transcription is blocked by STAT5, and later in dendritic cells and cancer cell lines (15–17). Further studies are needed to determine whether other STATs engage in this type of head-to-head competition and the question of how STAT-mediated transcriptional inhibition works, whether it reflects direct regulation of the loci themselves or induction of secondary agents (i.e.…”