USP5 promotes breast cancer cell proliferation and metastasis by stabilizing HIF2α

Hypoxia-inducible factor 2 alpha (HIF2 alpha) plays a pivotal role in breast tumor growth and metastasis. However, the regulatory mechanisms of HIF2 alpha protein stability remain poorly understood. The precise role of the deubiquitinase (DUB) ubiquitin-specific peptidase 5 (USP5) in breast cancer and the underlying mechanism remains largely unknown. Here, we identified USP5 as a novel DUB for HIF2 alpha. Physically, USP5 interacts with HIF2 alpha and protects HIF2 alpha from ubiquitin-proteasome degradation, thereby promoting the transcription of HIF2 alpha target genes, such as SLC2A1, PLOD2, P4HA1, and VEGFA. USP5 ablation impairs breast cancer cells proliferation, colony formation, migration, and invasion. Moreover, USP5 is highly expressed in breast cancer, and the protein levels of USP5 are positively correlated with HIF2 alpha protein levels in human breast cancer tissues. Importantly, high levels of USP5 leads to poor clinical outcome in patients with breast cancer. Collectively, USP5 stabilizes HIF2 alpha through its DUB activity and provides a potential therapeutic target for breast cancer.