Yonsei University School of Medicine, Seoul-t'ukpyolsi, Republic of Korea
Seo-Hyun Choi (Yonsei University School of Medicine)| Man-Wook Hur (Yonsei University School of Medicine)
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.