WWP1介导膀胱癌细胞中HIPK3的泛素化和降解。

Chen Haichao, Na Xinyu, Hu Pengcheng, Ma Qi, Yu Rui

Department of Urology, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang Province, China.

Department of Urology, Zhenhai People's Hospital, Ningbo, Zhejiang Province, China.

J Biol Chem. 2025 Apr 23;301(6):108528. doi: 10.1016/j.jbc.2025.108528.

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.

蛋白质稳态主要由翻译后修饰（PTM）调控。HIPK3在多种癌症中被公认为是一种肿瘤抑制因子。然而，PTM对HIPK3的影响仍未得到充分研究。本研究确定WWP1为靶向HIPK3的E3泛素连接酶，表明WWP1通过促进HIPK3的泛素化来下调其蛋白水平。从机制上讲，WWP1直接与HIPK3相互作用，促进K1187位点的K48连接的多聚泛素化。WWP1/HIPK3轴通过调节JNK信号通路来调节癌细胞的化学敏感性。此外，发现Myc作为转录因子可增强WWP1的表达。这些发现为PTM水平上HIPK3的调控提供了新的见解。