USP5 promotes breast cancer cell proliferation and metastasis by stabilizing HIF2α

Abstract

Hypoxia‐inducible factor 2α (HIF2α) plays a pivotal role in breast tumor growth and metastasis. However, the regulatory mechanisms of HIF2α 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 HIF2α. Physically, USP5 interacts with HIF2α and protects HIF2α from ubiquitin‐proteasome degradation, thereby promoting the transcription of HIF2α 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 HIF2α 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 HIF2α through its DUB activity and provides a potential therapeutic target for breast cancer.

A pan-cancer analysis of USP5: its diagnostic, prognostic and immunological roles in human cancers

“…In addition, we further analyzed the association between the expression level of USP5 and DSS or PFI of cancer patients, and we proved that on the whole, USP5 exhibited risk role in MESO and UVM for OS, DSS and PFI, in LUAD and SKCM for OS and DSS and in COAD for DSS and PFI. In addition to the previous reported negative association between USP5 and the progression of BRCA [13], BLCA [27], CRC[28], GBM [21], LIHC [17], melanoma [29], NSCLC [15,26], OV [22] and PAAD [23], our result rst showed that USP5 may emerge as a novel biomarker for predicting the prognosis of ACC, LAML and MESO, especially MESO. These results suggested that USP5 had important diagnostic and prognostic implications in various cancers, and may serve as a therapeutic target for precision oncology.…”

“…Based on our results, USP5 had a certain diagnostic accuracy (AUC > 0.7) in 20 cancer types, especially in predicting BRCA, CHOL, DLBC, LGG, LUSC, PAAD and THYM (AUC > 0.9), indicating the potential clinical application value of USP5 as a reliable diagnostic biomarker. Meanwhile, as a unique member of DUBs, USP5 could regulate the stability of some key tumor-regulating molecular such as, HIF2α in BRCA [13], CyclinD1 in GBM [21], SLUG in LIHC [17], HDAC2 in OV [22], STAT3 [23], WT1 [20] and FOXM1 [24] in PAAD and β-catenin [25], PD-L1[26] and CCND1 [15] in NSCLC to promote cancer progression, and our ROC curve analysis showed the AUC of 0.905 in BRCA, 0.852 in GBM, 0.891 in LIHC, 0.820 in OV, 0.980 in PAAD and 0.946 in LUSC. Thus, the combination of USP5 with these tumor-related molecular separately may signi cantly improve the diagnostic accuracy for the above cancers.…”

“…Additionally, via the functional enrichment analyses of USP5 co-expressed genes, we showed that "spliceosome" and "RNA splicing" may be the critical mechanism for USP5 to involve in pan-cancer. Previous studies had demonstrated that USP5 could regulate cancers by mediating EMT, such as, in LIHC by stabilizing SLUG [17], in NSCLC by stabilizing β-catenin [25] and in BRCA by stabilizing HIF2α [13]. In addition, it had been found that silencing of USP5 may increase apoptosis and DNA damage to suppress the progression of PAAD [46].…”

“…As for the role of USP5 in cancer, it has attracted the attention from many researchers recently. The functional link between the aberrant USP5 expression and the development of various cancers such as breast cancer [13], lung cancer [14,15], colorectal cancer [16] and hepatocellular carcinoma [17] has been established by many studies. Meanwhile, USP5 has been demonstrated to be closely correlated with some key molecules and pathways regulating cancer, which indicates the potential value of USP5 as a novel treatment target for cancer [18].…”

EOAI, a ubiquitin-specific peptidase 5 inhibitor, prevents non-small cell lung cancer progression by inducing DNA damage

“…Like other USP family deubiquitination enzymes, USP5 is involved in the occurrence and development of various cancers. It has been reported that USP5 overexpressed in many tumors and implicated in its progression, including pancreatic cancer [ 6 ], breast cancer [ 7 ], and glioblastoma [ 8 ]. Wang S et al found that USP5 protein has five key domains, including the implicit ZnF domain and c-box domain, that interact with c-Maf, demonstrating that c-Maf is a crucial factor in USP5-mediated myeloma cell proliferation and survival [ 9 ].…”