Sherry-Lynes Maureen M, Sengupta Sejuti, Kulkarni Shreya, Cochran Brent H
Graduate Program in Cell and Molecular Physiology, Sackler School of Graduate Biomedical Sciences and Dept. of Developmental,Molecular, and Chemical Biology Tufts University School of Medicine Boston, MA, United States of America.
PLoS One. 2017 Apr 6;12(4):e0174775. doi: 10.1371/journal.pone.0174775. eCollection 2017.
The growth factor and cytokine regulated transcription factor STAT3 is required for the self-renewal 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.
生长因子和细胞因子调节的转录因子STAT3是包括胶质母细胞瘤肿瘤干细胞在内的多种干细胞自我更新所必需的。在此我们表明，STAT3抑制导致组蛋白H3K27me2/3去甲基化酶Jmjd3（KDM6B）上调，其可逆转多梳复合物介导的组织特异性基因的抑制。STAT3与Jmjd3启动子结合，表明Jmjd3是STAT3的直接靶标。Jmjd3的过表达减缓胶质母细胞瘤干细胞生长和神经球形成，而Jmjd3的敲低挽救了STAT3抑制剂诱导的神经球形成缺陷。与该观察结果一致，STAT3抑制导致神经分化基因如Myt1、FGF21和GDF15的组蛋白H3K27去甲基化。这些结果表明，STAT3对Jmjd3的调节维持了分化特异性基因的抑制，因此对于正常神经干细胞和胶质母细胞瘤干细胞自我更新的维持很重要。
