Open AccessCUL4B Promotes Breast Carcinogenesis by Coordinating with Transcriptional Repressor Complexes in Response to Hypoxia Signaling Pathway
Author(s) -
Huang Wei,
Zhang Jingyao,
Huo Miaomiao,
Gao Jie,
Yang Tianshu,
Yin Xin,
Wang Pei,
Leng Shuai,
Feng Dandan,
Chen Yang,
Yang Yang,
Wang Yan
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.202001515
Subject(s) - corepressor , transcription factor , cancer research , carcinogenesis , gata3 , microbiology and biotechnology , histone deacetylase , ubiquitin ligase , epithelial–mesenchymal transition , biology , chemistry , repressor , downregulation and upregulation , histone , cancer , ubiquitin , genetics , gene
Cullin4B (CUL4B) is a scaffold protein of the CUL4B‐Ring E3 ligase (CRL4B) complex. However, the role of CUL4B in the development of breast cancer remains poorly understood. Here it is shown that CRL4B interacts with multiple histone deacetylase (HDAC)‐containing corepressor complexes, including MTA1/NuRD, SIN3A, CoREST, and NcoR/SMRT complexes. It is demonstrated that CRL4B/NuRD(MTA1) complexes cooccupy the E‐cadherin and AXIN2 promoters, and could be recruited by transcription factors including Snail and ZEB2 to promote cell invasion and tumorigenesis both in vitro and in vivo. Remarkably, CUL4B responded to transformation and migration/invasion stimuli and is essential for multiple epithelial‐mesenchymal transition (EMT) signaling pathways such as hypoxia. Furthermore, the transcription of CUL4B is directedly activated by hypoxia‐inducible factor 1 α (HIF1 α ) and repressed by the ER α ‐GATA3 axis. Overexpressing of CUL4B successfully induced CSC‐like properties. Strikingly, CUL4B expression is markedly upregulated during breast cancer progression and correlated with poor prognosis. The results suggest that CUL4B lies at a critical crossroads between EMT and stem cell properties, supporting CUL4B as a potential novel target for the development of anti‐breast cancer therapy.