Stabilization of proto‐oncoprotein ZBTB7A by HSP90 is reversed by p53/KLHL20 proteasomal degradation system upon HSP90 inhibition

다국어 초록 (Multilingual Abstract)

ZBTB7A is overexpressed in many human cancers, and is considered a major oncogenic driver. ZBTB7A plays important roles in tumorigenesis by regulating transcription of genes involved in cell survival and proliferation, apoptosis, invasion, and migration/metastasis, key biological capabilities for development of human cancer. One critically unresolved issue is a lack of insight into the mechanisms underlying the aberrant expression and function of ZBTB7A in cancer cells. To that end, we found that HSP90 inhibition decreased ZBTB7A expression in a variety of human cancer cells. ZBTB7A interacts with and is stabilized by HSP90 by inhibition of the ubiquitin‐mediated proteasomal degradation pathway. Functional 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. ZBTB7A degradation resulted in derepression of ZBTB7A target genes regulating cell cycle and inhibition of cell proliferation. Our study also revealed a novel function of p53 counteracting proto‐oncoprotein ZBTB7A.