BAP1-mediated MAFF deubiquitylation regulates tumor growth and is associated with adverse outcomes in colorectal cancer

• Published in: European journal of cancer (1990) Vol. 210; p. 114278
• Main Authors: Xie, Zhongdong, Lin, Hanbin, Huang, Ying, Wang, Xiaojie, Lin, Hongyue, Xu, Meifang, Wu, Jiashu, Wu, Yuecheng, Shen, Hao, Zhang, Qiongying, Chen, Jinhua, Deng, Yu, Xu, Zongbin, Chen, Zhiping, Lin, Yu, Han, Yuting, Lin, Lin, Yan, Linzhu, Li, Qingyun, Lin, Xinjian, Chi, Pan
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.10.2024
• Subjects: Animals; BAP1; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Cell Line, Tumor; Cell Proliferation; Colorectal cancer; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; DUSP5; ERK signaling; Female; Gene Expression Regulation, Neoplastic; Humans; MAFF; Male; Mice; Middle Aged; Prognosis; Proteasome Endopeptidase Complex - metabolism; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Ubiquitin Thiolesterase - genetics; Ubiquitin Thiolesterase - metabolism; Ubiquitination; DUSP5; DUBs; OS; IHC; Colorectal cancer; Co-IP; DFS; GEO; CRC; MAFF; ERK signaling; BAP1; ERK
• ISSN: 0959-8049; 1879-0852; 1879-0852
• DOI: 10.1016/j.ejca.2024.114278

Despite improvements in colorectal cancer (CRC) treatment, the prognosis for advanced CRC patients remains poor. Disruption of protein stability is one of the important factors in cancer development and progression. In this study, we aim to identify and analyze novel dysregulated proteins in CRC, assessing their significance and the mechanisms. Using quantitative proteomics, expression pattern analysis, and gain-of-function/loss-of-function experiments, we identify novel functional protein dysregulated by ubiquitin-proteasome axis in CRC. Prognostic significance was evaluated in a training cohort of 546 patients and externally validated in 794 patients. Mechanistic insights are gained through molecular biology experiments, deubiquitinating enzymes (DUBs) expression library screening, and RNA sequencing. MAFF protein emerged as the top novel candidate substrate regulated by ubiquitin-proteasome in CRC. MAFF protein was preferentially downregulated in CRC compared to adjacent normal tissues. More importantly, multicenter cohort study identified reduced MAFF protein expression as an independent predictor of overall and disease-free survival in CRC patients. The in vitro and vivo assays showed that MAFF overexpression inhibited CRC growth, while its knockdown had the opposite effect. Intriguingly, we found the abnormal expression of MAFF protein was predominantly regulated via ubiquitination of MAFF, with K48-ubiquitin being dominant. BAP1 as a nuclear deubiquitinating enzyme (DUB), bound to and deubiquitinated MAFF, thereby stabilizing it. Such stabilization upregulated DUSP5 expression, resulting in the inhibition of ERK phosphorylation. This study describes a novel BAP1-MAFF signaling axis which is crucial for CRC growth, potentially serving as a therapeutic target and a promising prognostic biomarker for CRC. •MAFF protein is preferentially downregulated in CRC.•MAFF protein signature segregates CRC patient survival.•The K48-linked ubiquitination affects aberrant MAFF expression in CRC.•BAP1 suppresses CRC growth via deubiquitylation of MAFF at K92 and K110 residue.•DUSP5 is required for MAFF’s CRC growth suppression through ERK phosphorylation.