2. Academic Validation
  3. BAP1-mediated MAFF deubiquitylation regulates tumor growth and is associated with adverse outcomes in colorectal cancer

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

  • Eur J Cancer. 2024 Aug 10:210:114278. doi: 10.1016/j.ejca.2024.114278.
Zhongdong Xie 1,  Hanbin Lin 2,  Ying Huang 1,  Xiaojie Wang 1,  Hongyue Lin 3,  Meifang Xu 4,  Jiashu Wu 5,  Yuecheng Wu 2,  Hao Shen 6,  Qiongying Zhang 7,  Jinhua Chen 8,  Yu Deng 1,  Zongbin Xu 1,  Zhiping Chen 1,  Yu Lin 1,  Yuting Han 2,  Lin Lin 4,  Linzhu Yan 1,  Qingyun Li 1,  Xinjian Lin 9,  Pan Chi 10
Affiliations

Affiliations

  • 1 Department of Colorectal Surgery, Union Hospital, Fujian Medical University, Fuzhou, China.
  • 2 Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China.
  • 3 Department of General Surgery, Affiliated Quanzhou First Hospital of Fujian Medical University, Quanzhou, China.
  • 4 Department of Pathology, Union Hospital, Fujian Medical University, Fuzhou, China.
  • 5 Department of Science and Technology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
  • 6 Department of Navy Environmental and Occupational Health, Naval Medical University, Shanghai, China.
  • 7 Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
  • 8 Follow up Center, Union Hospital, Fujian Medical University, Fuzhou, China.
  • 9 Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China. Electronic address: xlin@fjmu.edu.cn.
  • 10 Department of Colorectal Surgery, Union Hospital, Fujian Medical University, Fuzhou, China. Electronic address: chipanfjxh@163.com.
PMID: 39151323 DOI: 10.1016/j.ejca.2024.114278
Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords

BAP1; Colorectal cancer; DUSP5; ERK signaling; MAFF.

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