Deubiquitinase USP53 suppressed tumorigenesis of colorectal cancer cells by mediating deubiquitination of MORF4L1

Colorectal cancer is a common malignant tumor worldwide. Ubiquitin-specific proteases 53 (USP53) is a deubiquitinase that plays tumor-suppressing roles in multiple cancers. The analysis from databank showed that USP53 was downregulated in colorectal cancer specimens, and patients with USP53 low expression displayed poorer survival. This study aims to investigate the role of USP53 in colorectal cancer. Our clinical data displayed the low expression of USP53, compared with paired para-carcinoma tissues. Gain- and loss-of-function experiments firstly demonstrated that the overexpression of USP53 suppressed growth of colorectal cancer cells in vivo and in vitro , and aggravated bleomycin-induced cell damage. The silencing of USP53 played opposite roles. Through immunoprecipitation-liquid chromatogram/mass spectrum (IP-LC/MS) and ubiquitylome analysis, mortality factor 4-like protein 1 (MORF4L1) was screened as the potential substrate of USP53. The USP53 and MORF4L1 protein levels were positively related in colorectal cancer samples. USP53 bound to MORF4L1 and intercepted its ubiquitination and degradation, and the K249 and K227 of MORF4L1 protein were identified as the key sites. MORF4L1 was decreased in colorectal cancer samples, and patients with low MORF4L1 expression also exhibited poorer survival. Enhanced expression of MORF4L1 alleviated proliferation of colorectal cancer cells, and the effects of shUSP53 on colorectal cancer cells were abrogated by MORF4L1. In conclusion, USP53 suppressed growth of colorectal cancer cells by catalyzing the deubiquitination of MORF4L1. These findings may provide novel diagnostic markers or therapeutic targets for colorectal cancer in clinic.