Ubiquitin-specific peptidase 54 (USP54)

Ubiquitin-specific peptidase 54 (USP54) is a member of the ubiquitin-specific protease (USP) family of cysteine-type deubiquitinating enzymes. It is classified as a protein-coding gene located on chromosome 10. USP54 mediates the removal of ubiquitin from target proteins, helping to maintain protein stability and regulate cellular processes such as cell cycle and apoptosis. USP54 plays a role in modulating the epidermal growth factor receptor (EGFR) pathway by altering its ubiquitination status—particularly in the context of resistance to EGFR-targeted drugs like gefitinib in non-small cell lung cancer (NSCLC). Evidence suggests that USP54 promotes tumorigenesis and therapy resistance in colorectal cancer, melanoma, NSCLC, and prostate cancer. Although it was initially considered catalytically inactive, subsequent studies showed its functional involvement in cancer progression and drug response. USP54 is considered a potential therapeutic target in oncology, especially for overcoming drug resistance. No approved drugs currently target USP54 directly, but its modulation offers promise for future cancer therapy strategies.

Other names

Ubiquitin carboxyl-terminal hydrolase 54USP54C10orf29FLJ37318bA137L10.3bA137L10.4Ubiquitin-specific proteinase 54

Drugs that inhibit USP54 function enhance EGFR ubiquitination and degradation, leading to increased cell cycle arrest and apoptosis (shown for gefitinib in NSCLC models). Suppressing USP54 sensitizes resistant cancer cells to EGFR inhibitors by destabilizing EGFR signaling.