1. Academic Validation
  2. The Dual Function of KDM5C in Both Gene Transcriptional Activation and Repression Promotes Breast Cancer Cell Growth and Tumorigenesis

The Dual Function of KDM5C in Both Gene Transcriptional Activation and Repression Promotes Breast Cancer Cell Growth and Tumorigenesis

  • Adv Sci (Weinh). 2021 Feb 18;8(9):2004635. doi: 10.1002/advs.202004635.
Hai-Feng Shen 1 Wen-Juan Zhang 1 Ying Huang 1 Yao-Hui He 1 Guo-Sheng Hu 1 Lei Wang 1 Bing-Ling Peng 1 Jia Yi 1 Ting-Ting Li 2 Rui Rong 2 Xiao-Yan Chen 3 Jun-Yi Liu 2 Wen-Juan Li 1 Kenny Ohgi 4 Shao-Wei Li 2 Michael G Rosenfeld 4 Wen Liu 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Cellular Stress Biology Fujian Provincial Key Laboratory of Innovative Drug Target Research School of Pharmaceutical Sciences Xiamen University Xiang'an South Road Xiamen Fujian 361102 China.
  • 2 State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics Xiamen University Xiang'an South Road Xiamen Fujian 361102 China.
  • 3 School of Life Sciences Xiamen University Xiang'an South Road Xiamen Fujian 361102 China.
  • 4 Howard Hughes Medical Institute Department of Medicine University of California 9500 Gilman Drive La Jolla San Diego CA 92093 USA.
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 (ERα)-target genes, and meanwhile suppresses type I interferons (IFNs) and IFN-stimulated genes (ISGs) to promote ERα-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 ERα-target genes, while inhibits TBK1 phosphorylation in the cytosol to repress type I IFNs and ISGs. Pharmacological inhibition of both ERα 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.

Keywords

Jumonji C domain‐containing protein; breast cancer; estrogen and estrogen receptor; type I interferon.

Figures
Products