Neddylation of HER2 Inhibits its Protein Degradation and promotes Breast Cancer Progression

HER2, a transmembrane receptor with intrinsic tyrosine kinase activity, is overexpressed in approximately 25% of human breast cancers. This study demonstrates that HER2 neddylation, a novel post-translational modification, regulates its expression and oncogenic activity. NEDD8 and NAE1, key components of the neddylation pathway, are present in breast cancer specimens, and their overexpression correlates with HER2 expression. Neddylation inhibition promotes HER2 protein degradation by increasing its ubiquitination. HER2 overexpression counteracts the growth-suppressing effects of neddylation depletion. Inhibition of neddylation synergizes with trastuzumab to suppress HER2-positive breast cancer growth. These findings suggest that NEDD8-dependent HER2 neddylation is a novel therapeutic target for breast cancer.

Xiaohong Xia, Tumei Hu, Xiaoyue He, Yuan Liu, Cuifu Yu, Weiyao Kong, Yuning Liao, Daolin Tang, Jinbao Liu, Hongbiao Huang