期刊
ADVANCED SCIENCE
卷 8, 期 10, 页码 -出版社
WILEY
DOI: 10.1002/advs.202001515
关键词
breast cancer; cancer stem cell; CUL4B; epithelial‐ mesenchymal transition; HIF1A
资金
- National Natural Science Foundation of China [41931291, 81773017, 81902960]
- Major State Basic Research Development Program of China [2016YFA0102400]
CUL4B is a scaffold protein of the CRL4B complex and interacts with multiple corepressor complexes, playing a role in breast cancer development by cooccupying promoters and promoting cell invasion with transcription factors. The expression of CUL4B is regulated by hypoxia and estrogen receptor signaling, and its overexpression induces CSC-like properties, suggesting it as a potential target for anti-breast cancer therapy.
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 alpha (HIF1 alpha) and repressed by the ER alpha-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.
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