Open AccessThe Dual Function of KDM5C in Both Gene Transcriptional Activation and Repression Promotes Breast Cancer Cell Growth and Tumorigenesis
Author(s) -
Shen Haifeng,
Zhang Wenjuan,
Huang Ying,
He Yaohui,
Hu Guosheng,
Wang Lei,
Peng Bingling,
Yi Jia,
Li Tingting,
Rong Rui,
Chen Xiaoyan,
Liu Junyi,
Li Wenjuan,
Ohgi Kenny,
Li ShaoWei,
Rosenfeld Michael G.,
Liu Wen
Publication year - 2021
Publication title -
advanced science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.388
H-Index - 100
ISSN - 2198-3844
DOI - 10.1002/advs.202004635
Subject(s) - carcinogenesis , epigenetics , biology , repressor , demethylase , corepressor , enhancer , activator (genetics) , cell growth , cancer research , microbiology and biotechnology , transcription factor , gene , genetics
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.