pVHL promotes lysosomal degradation of YAP in lung adenocarcinoma

• Published in: Cellular signalling 2021-07, Vol.83, p.110002-110002, Article 110002
• Main Authors: Hu, Lan, Wu, Hao, Jiang, Tian, Kuang, Mengzhen, Liu, Bo, Guo, Xinying, He, Daochuan, Chen, Mengqian, Gu, Jie, Gu, Jianxin, Chang, Lei, Feng, Mingxiang, Ruan, Yuanyuan
• Format: Article
• Language: English
• Subjects: A549 Cells; Adenocarcinoma of Lung - genetics; Adenocarcinoma of Lung - metabolism; Adenocarcinoma of Lung - pathology; Carcinogenesis - genetics; Carcinogenesis - metabolism; Humans; Lung adenocarcinoma; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Lysosomal degradation; Lysosomes - genetics; Lysosomes - metabolism; O-GlcNAcylation; Proteolysis; pVHL; Von Hippel-Lindau Tumor Suppressor Protein - genetics; Von Hippel-Lindau Tumor Suppressor Protein - metabolism; YAP; YAP-Signaling Proteins - genetics; YAP-Signaling Proteins - metabolism
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2021.110002

Yes-associated protein (YAP) is a vital transcriptional co-activator that activates cell proliferation and evasion of apoptosis for the promotion of tumorigenesis. The von Hippel-Lindau tumor suppressor protein (pVHL), as a critical component of E3 ubiquitin ligase, targets various substrates to regulate tumor progression. However, the precise molecular mechanisms of pVHL during tumorigenesis remain largely unclear. Herein, we found that there was a significant negative correlation between pVHL and YAP at protein level in the TCGA-LUAD dataset and our cohort. Over-expression of pVHL decreased YAP protein expression and reduced its transcriptional activity. Further study indicated that pVHL did not affect YAP mRNA level but decreased YAP protein stability in a lysosome-dependent manner. In addition, the pVHL-mediated degradation of YAP inhibited cellular proliferation, migration, and enhanced chemosensitivity to cisplatin in lung adenocarcinoma cells. Interestingly, the pVHL-mediated YAP degradation was blocked by elevated O-GlcNAcylation. Collectively, our findings demonstrate that pVHL modulates the lysosomal degradation of YAP, and may provide more clues to better understanding the tumor suppressive effects of pVHL. •pVHL decreases YAP protein expression via the lysosomal degradation pathway.•YAP suppression is involved in the anti-tumor effect of pVHL in lung adenocarcinoma.•pVHL-mediated YAP repression is blocked by O-GlcNAcylation.