UBR5 mediates colorectal cancer chemoresistance by attenuating ferroptosis via Lys 11 ubiquitin-dependent stabilization of Smad3-SLC7A11 signaling
Mei Song,
Shuting Huang,
Xiaoxue Wu,
Ziyi Zhao,
Xiaoting Liu,
Chong Wu,
Mengru Wang,
Jialing Gao,
Zunfu Ke,
Xiaojing Ma,
Weiling He
Affiliations
Mei Song
Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510275, China; Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510275, China; Corresponding author. Sun Yat-Sen University, Guangzhou, Guangdong 510275, China.
Shuting Huang
School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, 510275, China
Xiaoxue Wu
Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510275, China
Ziyi Zhao
Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510275, China
Xiaoting Liu
Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510275, China
Chong Wu
Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510275, China
Mengru Wang
Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510275, China
Jialing Gao
Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510275, China
Zunfu Ke
Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510275, China
Xiaojing Ma
Department of Microbiology and Immunology, Weill Cornell Medicine, NY, 10065, USA
Weiling He
Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510275, China; School of Medicine, Xiang'an Hospital of Xiamen University, Xiamen University, Xiamen, Fujian, 361000, China; Corresponding author. Sun Yat-Sen University, Guangzhou, Guangdong 510275, China.
Chemoresistance remains a principal culprit for the treatment failure in colorectal cancer (CRC), especially for patients with recurrent or metastatic disease. Deciphering the molecular basis of chemoresistance may lead to novel therapeutic strategies for this fatal disease. Here, UBR5, an E3 ubiquitin ligase frequently overexpressed in human CRC, is demonstrated to mediate chemoresistance principally by inhibiting ferroptosis. Paradoxically, UBR5 shields oxaliplatin-activated Smad3 from proteasome-dependent degradation via Lys 11-linked polyubiquitination. This novel chemical modification of Smad3 facilitates the transcriptional repression of ATF3, induction of SLC7A11 and inhibition of ferroptosis, contributing to chemoresistance. Consequently, targeting UBR5 in combination with a ferroptosis inducer synergistically sensitizes CRC to oxaliplatin-induced cell death and control of tumor growth. This study reveals, for the first time, a major clinically relevant chemoresistance mechanism in CRC mediated by UBR5 in sustaining TGFβ-Smad3 signaling and tuning ferroptosis, unveiling its potential as a viable therapeutic target for chemosensitization.
