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

ABSTRACT

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.