癌变
表观遗传学
生物
抑制因子
脱甲基酶
加压器
增强子
激活剂(遗传学)
细胞生长
癌症研究
细胞生物学
转录因子
基因
遗传学
作者
Haifeng Shen,Wenjuan Zhang,Ying Huang,Yaohui He,Guo-Sheng Hu,Li Wang,Bing‐ling Peng,Yi Jia,Ting‐ting Li,Rui Rong,Xiao‐yan Chen,Jun‐yi Liu,Wenjuan Li,Kenny Ohgi,Shaowei Li,Michael G. Rosenfeld,Wen Liu
标识
DOI:10.1002/advs.202004635
摘要
Abstract Emerging evidence suggested that epigenetic regulators can exhibit both activator and repressor activities in gene transcriptional regulation and disease development, such as cancer. However, how these dual activities are regulated and coordinated in specific cellular contexts remains elusive. Here, it is reported that KDM5C, a repressive histone demethylase, unexpectedly activates estrogen receptor alpha (ER α )‐target genes, and meanwhile suppresses type I interferons (IFNs) and IFN‐stimulated genes (ISGs) to promote ER α ‐positive breast cancer cell growth and tumorigenesis. KDM5C‐interacting protein, ZMYND8, is found to be involved in both processes. Mechanistically, KDM5C binds to active enhancers and recruits the P‐TEFb complex to activate ER α ‐target genes, while inhibits TBK1 phosphorylation in the cytosol to repress type I IFNs and ISGs. Pharmacological inhibition of both ER α and KDM5C is effective in inhibiting cell growth and tumorigenesis. Taken together, it is revealed that the dual activator and repressor nature of an epigenetic regulator together contributes to cancer development.
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