Implications of STAT3 and STAT5 signaling on gene regulation and chromatin remodeling in hematopoietic cancer

Abstract

STAT3 and STAT5 proteins are oncogenic downstream mediators of the JAK–STAT pathway. Deregulated STAT3 and STAT5 signaling promotes cancer cell proliferation and survival in conjunction with other core cancer pathways. Nuclear phosphorylated STAT3 and STAT5 regulate cell-type-specific transcription profiles via binding to promoter elements and exert more complex functions involving interaction with various transcriptional coactivators or corepressors and chromatin remodeling proteins. The JAK–STAT pathway can rapidly reshape the chromatin landscape upon cytokine, hormone, or growth factor stimulation and unphosphorylated STAT proteins also appear to be functional with respect to regulating chromatin accessibility. Notably, cancer genome landscape studies have implicated mutations in various epigenetic modifiers as well as the JAK–STAT pathway as underlying causes of many cancers, particularly acute leukemia and lymphomas. However, it is incompletely understood how mutations within these pathways can interact and synergize to promote cancer. We summarize the current knowledge of oncogenic STAT3 and STAT5 functions downstream of cytokine signaling and provide details on prerequisites for DNA binding and gene transcription. We also discuss key interactions of STAT3 and STAT5 with chromatin remodeling factors such as DNA methyltransferases, histone modifiers, cofactors, corepressors, and other transcription factors.

STAT3 activates MSK1-mediated histone H3 phosphorylation to promote NFAT signaling in gastric carcinogenesis

“…As the most important oncogenic downstream mediator of the JAK-STAT pathway, deregulated STAT3 has been demonstrated to promote cancer progression mainly through its role as transcription factor. Recent studies illustrated that STAT3 can also affect gene expression via chromatin remodelling, especially epigenetic modifications 42 . STAT3 associates with critical epigenetic modifiers, such as DNA methyltransferase DNMT1 and histone modifiers (EZH2, HAT1, etc.…”

“…STAT3 associates with critical epigenetic modifiers, such as DNA methyltransferase DNMT1 and histone modifiers (EZH2, HAT1, etc. ), to facilitate gene silencing or activation 42 . With interaction, histone-modifying enzymes also modify STAT3, including acetylation and methylation changes, which has important consequences for target gene transcription 42 .…”

“…), to facilitate gene silencing or activation 42 . With interaction, histone-modifying enzymes also modify STAT3, including acetylation and methylation changes, which has important consequences for target gene transcription 42 . Interestingly, it was recently reported that STAT3 can directly regulate the transcription of some crucial epigenetic enzymes (DNMT1, EZH2, JMJD3), adding another functional level of STAT3 as an important regulator of global epigenetic modifications and chromatin accessibilities [21][22][23] .…”

Chaperoning STAT3/5 by Heat Shock Proteins: Interest of Their Targeting in Cancer Therapy

“…Interestingly, the phosphorylation state of STAT3 was not altered in the absence of HSP27 in placental explants, suggesting a role in protein protection from proteasomal degradation [137]. This could be explained by the fact that STAT3 and STAT5 have a relatively low thermodynamic stability as isolated proteins and are thus more prone to aggregation, which would be limited by HSP27 [124]. Given the importance of STAT3 in embryonic development (STAT3 knock-out mice have a lethal embryonic phenotype) [138], this finding revealed the critical role of HSP27 in this process.…”

“…Indeed, the STAT3/5 complexes and HSP90 have been shown to colocalize in MYC and in CCND2 promoters [69]. Furthermore, nuclear hormone receptors form multiprotein complexes with STAT3 and STAT5 [122,123], which together with HSPs could contribute to chromatin landscaping [124].…”