Post-translational regulation of proto-oncogene ZBTB7A expression by p53 status in cancer cells: HSP90-dependent stabilization vs. p53-KLHL20-ubiquitin proteasomal degradation

ZBTB7A overexpressed in many human cancers is a major oncogenic driver. ZBTB7A promotes tumorigenesis by regulating transcription of the genes involved in cell survival and proliferation, apoptosis, invasion, and migration/metastasis. One unresolved issue is the mechanism underlying the aberrant ove...

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Published in:Biochimica et biophysica acta. Gene regulatory mechanisms 2023-06, Vol.1866 (2), p.194931-194931, Article 194931
Main Authors: Choi, Seo-Hyun, Cho, Su-Yeon, Park, Sun Young, Hur, Man-Wook
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - genetics
Cell Line, Tumor
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
HSP90
Humans
KLHL20
Neoplasms - genetics
p53
Proto-Oncogenes
Proto-oncoprotein
Transcription Factors - metabolism
Tumor Suppressor Protein p53 - genetics
Tumor Suppressor Protein p53 - metabolism
Ubiquitin - metabolism
Ubiquitin-Protein Ligases - genetics
Ubiquitin-Protein Ligases - metabolism
Ubiquitination
ZBTB7A
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Summary:ZBTB7A overexpressed in many human cancers is a major oncogenic driver. ZBTB7A promotes tumorigenesis by regulating transcription of the genes involved in cell survival and proliferation, apoptosis, invasion, and migration/metastasis. One unresolved issue is the mechanism underlying the aberrant overexpression of ZBTB7A in cancer cells. Interestingly, inhibition of HSP90 decreased ZBTB7A expression in a variety of human cancer cells. ZBTB7A interacts with and is stabilized by HSP90. Inhibition of HSP90 by 17-AAG resulted in p53-dependent proteolysis of ZBTB7A via increased p53 expression and upregulation of the CUL3-dependent E3 ubiquitin ligase, KLHL20. Down-regulation of ZBTB7A resulted in the derepression of a major negative regulator of cell cycle progression, p21/CDKN1A. We discovered a new function of p53 regulating ZBTB7A expression through KLHL20-E3 ligase and proteasomal protein degradation system.
ISSN:1874-9399
1876-4320
DOI:10.1016/j.bbagrm.2023.194931