Regulation of the JMJD3 (KDM6B) histone demethylase in glioblastoma stem cells by STAT3

Abstract

The growth factor and cytokine regulated transcription factor STAT3 is required for the selfrenewal of several stem cell types including tumor stem cells from glioblastoma. Here we show that STAT3 inhibition leads to the upregulation of the histone H3K27me2/3 demethylase Jmjd3 (KDM6B), which can reverse polycomb complex-mediated repression of tissue specific genes. STAT3 binds to the Jmjd3 promoter, suggesting that Jmjd3 is a direct target of STAT3. Overexpression of Jmjd3 slows glioblastoma stem cell growth and neurosphere formation, whereas knockdown of Jmjd3 rescues the STAT3 inhibitor-induced neurosphere formation defect. Consistent with this observation, STAT3 inhibition leads to histone H3K27 demethylation of neural differentiation genes, such as Myt1, FGF21, and GDF15. These results demonstrate that the regulation of Jmjd3 by STAT3 maintains repression of differentiation specific genes and is therefore important for the maintenance of self-renewal of normal neural and glioblastoma stem cells.

KDM6B is an androgen regulated gene and plays oncogenic roles by demethylating H3K27me3 at cyclin D1 promoter in prostate cancer

“…KDM6B is an inducible histone demethylase and its expression was shown to be mediated by NF-κB and signal transducer and activator of transcription 3 in previous reports 33,34 . As mentioned above, we found a negative association between KDM6B and PSA.…”

Cancer stem cells and oral cancer: insights into molecular mechanisms and therapeutic approaches

“…Convincing documents demonstrated that histone demethylases involve in different cellular procedures such as carcinogenesis, cell fate selection, and cell differentiation [120][121][122]. Currently, the increasing trend of documents showed the essential contribution of histone demethylases such as JARID1, KDM4, LSD1, KDM6B, KDM6A, KMD3, KDM5, and Jumonji domain-consisting of protein 6 (JMJD6) to the cancer stem cell phenotype in several kinds of cancers [61,[123][124][125][126][127][128][129][130]. JMJD6 has been represented as a new molecular modulator of OCSCs [61].…”

GDF‐15: Diagnostic, prognostic, and therapeutic significance in glioblastoma multiforme

“…STAT3 is critical in the proliferation and multipotency of the glioblastoma stem cell (G. H. Li et al, 2010; Sherry et al, 2009). Inhibiting STAT3 can induce H3K27 demethylation, as well as a further expression of target genes linked to GBM‐SC neural differentiation (Sherry‐Lynes et al, 2017). It preserves healthy neural and glioblastoma stem cells in a proliferative and self‐renewing condition by suppressing the histone demethylase Jmjd3 (Sherry‐Lynes et al, 2017).…”

“…Inhibiting STAT3 can induce H3K27 demethylation, as well as a further expression of target genes linked to GBM‐SC neural differentiation (Sherry‐Lynes et al, 2017). It preserves healthy neural and glioblastoma stem cells in a proliferative and self‐renewing condition by suppressing the histone demethylase Jmjd3 (Sherry‐Lynes et al, 2017). STAT3 inhibition was found to be irreversible in GBM‐SC (Sherry‐Lynes et al, 2017).…”

“…It preserves healthy neural and glioblastoma stem cells in a proliferative and self‐renewing condition by suppressing the histone demethylase Jmjd3 (Sherry‐Lynes et al, 2017). STAT3 inhibition was found to be irreversible in GBM‐SC (Sherry‐Lynes et al, 2017). Isochaihulactone (K8) activates GDF‐15 in glioblastoma (Tsai et al, 2017).…”