TRIM21 induces selective autophagic degradation of c- Myc and sensitizes regorafenib therapy in colorectal cancer

• 成果类型: Article
• 署名作者: Ye, Wen-Long; Huang, Long; Yang, Xiao-Qin; Wan, Shan; Gan, Wen-Juan; Yang, Yun; He, Xiao-Shun; Liu, Feng; Guo, Xin; Liu, Yi-Xuan; Hu, Guang; Li, Xiu-Ming; Shi, Wei-Yi; He, Kuang; Wu, Yue-Yue; Wu, Wen-Xin; Lu, Jun-Hou; Song, Yu; Qu, Chen-Jiang; Wu, Hua
• 署名单位: Soochow University - China; Soochow University - China; Soochow University - China; Soochow University - China; Soochow University - China
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-15344
• DOI: 10.1073/pnas.2406936121
• 发表日期: 2024-10-15
• 关键词: colon-cancer; n-myc; kras; inhibition; resistance; angiogenesis; activation; expression; lung

摘要

Kirsten rat sarcoma virus (KRAS) mutation is associated with malignant tumor transformation and drug resistance. However, the development of clinically effective targeted therapies for KRAS-mutant cancer has proven to be a formidable challenge. Here, we report that tripartite motif- containing protein 21 (TRIM21) functions as a target of extracellular signal- regulated kinase 2 (ERK2) in KRAS- mutant colorectal cancer (CRC), contributing to regorafenib therapy resistance. Mechanistically, TRIM21 directly interacts with and ubiquitinates v-myc avian myelocytomatosis viral oncogene homolog (c-Myc) at lysine 148 (K148) via K63- linkage, enabling c-Myc to be targeted to the autophagy machinery for degradation, ultimately resulting in the downregulation of enolase 2 expression and inhibition of glycolysis. However, mutant KRAS (KRAS/MT)- driven mitogen- activated protein kinase (MAPK) signaling leads to the phosphorylation of TRIM21 (p- TRIM21) at Threonine 396 (T396) by ERK2, disrupting the interaction between TRIM21 and c-Myc and thereby preventing c-Myc from targeting autophagy for degradation. This enhances glycolysis and contributes to regorafenib resistance. Clinically, high p- TRIM21 (T396) is associated with an unfavorable prognosis. Targeting TRIM21 to disrupt KRAS/MT- driven phosphorylation using the antidepressant vilazodone shows potential for enhancing the efficacy of regorafenib in treating KRAS- mutant CRC in preclinical models. These findings are instrumental for KRAS- mutant CRC treatment aiming at activating TRIM21- mediated selective autophagic degradation of c-Myc.