Hsp70 acts as a fine-switch that controls E3 ligase CHIP-mediated TAp63 and ΔNp63 ubiquitination and degradation

• Published in: Nucleic acids research 2021-03, Vol.49 (5), p.2740-2758
• Main Authors: Wu, H Helena, Wang, Benfan, Armstrong, Stephen R, Abuetabh, Yasser, Leng, Sarah, Roa, Wilson H Y, Atfi, Azeddine, Marchese, Adriano, Wilson, Beverly, Sergi, Consolato, Flores, Elsa R, Eisenstat, David D, Leng, Roger P
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Cell Line, Tumor; Cell Movement; Cells, Cultured; HSP70 Heat-Shock Proteins - metabolism; HSP70 Heat-Shock Proteins - physiology; Humans; Mice; Molecular Biology; Neoplasm Invasiveness; Neoplasms - metabolism; Neoplasms - mortality; Trans-Activators - metabolism; Transcription Factors - metabolism; Transcriptional Activation; Tumor Suppressor Proteins - metabolism; Ubiquitin-Protein Ligases - metabolism; Ubiquitination
• ISSN: 0305-1048; 1362-4962
• DOI: 10.1093/nar/gkab081

Abstract The major clinical problem in human cancer is metastasis. Metastases are the cause of 90% of human cancer deaths. TAp63 is a critical suppressor of tumorigenesis and metastasis. ΔNp63 acts as a dominant-negative inhibitor to block the function of p53 and TAp63. Although several ubiquitin E3 ligases have been reported to regulate p63 stability, the mechanism of p63 regulation remains partially understood. Herein, we show that CHIP, an E3 ligase with a U-box domain, physically interacts with p63 and promotes p63 degradation. Notably, Hsp70 depletion by siRNA stabilizes TAp63 in H1299 cells and destabilizes ΔNp63 in SCC9 cells. Loss of Hsp70 results in a reduction in the TAp63-CHIP interaction in H1299 cells and an increase in the interaction between ΔNp63 and CHIP in SCC9 cells. Our results reveal that Hsp70 acts as a molecular switch to control CHIP-mediated ubiquitination and degradation of p63 isoforms. Furthermore, regulation of p63 by the Hsp70-CHIP axis contributes to the migration and invasion of tumor cells. Hence, our findings demonstrate that Hsp70 is a crucial regulator of CHIP-mediated ubiquitination and degradation of p63 isoforms and identify a new pathway for maintaining TAp63 or ΔNp63 stability in cancers.