Abstract
Protein homeostasis is primarily regulated by post-translational modifications (PTMs). HIPK3 has been recognized as a tumor suppressor across various cancers. However, the impact of PTMs on HIPK3 remains insufficiently explored. This study identified WWP1 as an E3 ubiquitin ligase targeting HIPK3, demonstrating that WWP1 downregulates HIPK3 protein levels by facilitating its ubiquitination. Mechanistically, WWP1 directly interacts with HIPK3, promoting K48-linked polyubiquitination at the K1187 site. The WWP1/HIPK3 axis modulates cancer cell chemosensitivity through the regulation of the JNK signaling pathway. Additionally, Myc was found to act as a transcription factor, enhancing WWP1 expression. These findings offer novel insights into the regulation of HIPK3 at the PTM level.