文献类型：期刊文献

英文题名：DHODH is a synthetic lethal target in PIK3CA-mutant colorectal cancer

作者：Liang, Jun[1];Liu, Xi[1];Ni, Ziyun[2,3];Zhang, Sen[2,3];He, Xiangli[1];Wang, Lili[1];Huang, Yukun[1];Xu, Zhaomin[1];Xu, Zhongyu[1];Qian, Jiayi[1];Lu, Lixue[4];Abuduaini, Naijipu[2,3];Tian, Jing[5];Zeng, Minghua[6];Wang, Qi[7];Sun, Jing[4];Xie, Qiong[2,3];Wang, Yonghui[2,3];Lu, Weiqiang[8,9,10,11,12,13];Feng, Bo[2,3];Han, Bo[5];Huang, Jin[1]

机构：[1]East China Univ Sci Technol, Shanghai Frontiers Sci Ctr Optogenet Tech Cell Met, Optogenet & Synthet Biol Interdisciplinary Res Ctr, Shanghai Key Lab New Drug Design,State Key Lab Bio, Shanghai, Peoples R China;[2]Shanghai Jiao Tong Univ, Ruijin Hosp, Dept Gen Surg, Sch Med, Shanghai, Peoples R China;[3]Shanghai Jiao Tong Univ, Ruijin Hosp, Dept Pathol, Sch Med, Shanghai, Peoples R China;[4]Fudan Univ, Sch Pharm, Dept Med Chem, Shanghai, Peoples R China;[5]Shihezi Univ, Sch Pharm, Key Lab Xinjiang Phytomedicine Resource & Utilizat, Minist Educ,Inst Safflower Ind Res, Shihezi, Peoples R China;[6]Guangxi Normal Univ, Key Lab Chem & Mol Engn Med Resources, Guangxi Key Lab Chem & Mol Engn Med Resources, Minist Educ China,Sch Chem & Pharmaceut Sci, Guilin, Peoples R China;[7]Univ Engn Res Ctr Oncolyt & Nanosyst Dev, Dept Expt Res, Guangxi Key Lab Extremely Weak Magnet Field Canc M, Nanning, Peoples R China;[8]Hainan Med Univ, Hainan Acad Med Sci, Ctr Drug Discovery & Translat Med, Haikou, Hainan, Peoples R China;[9]East China Normal Univ, Inst Biomed Sci, Shanghai Key Lab Regulatory Biol, Shanghai, Peoples R China;[10]East China Normal Univ, Sch Life Sci, Shanghai, Peoples R China;[11]Shanghai Jiao Tong Univ, Sch Pharmaceut Sci, State Key Lab Innovat Immunotherapy, Shanghai, Peoples R China;[12]Hainan Med Univ, Engn Res Ctr Trop Med Innovat & Transformat, Hainan Prov Key Lab Res & Dev Trop Herbs, Minist Educ, Haikou, Peoples R China;[13]Hainan Med Univ, Sch Pharmaceut Sci, Haikou Key Lab Li Nationality Med, Haikou, Peoples R China

年份：2026

卷号：45

期号：8

外文期刊名：CELL REPORTS

收录：;Scopus(收录号：2-s2.0-105045485745);WOS:【SCI-EXPANDED(收录号:WOS:001836304000001)】；

基金：We thank Dr. Wenming Qin and Dr. Tingting Wu at SSRF beamline BL19U for assistance with data collection. This project was supported by the National Natural Science Foundation of China (grant nos. 82574463, 82173857, 82373913, and 82473763), the Translational Medicine National Science and Technology Infrastructure (Shanghai) 2024 Open Research Project (grant no. TMSK-2024-1 02), and the Shanghai Oriental Talent Plan Outstanding Project (grant no. BJJY2024021).

语种：英文

外文关键词：cancer stemness; colorectal cancer; DHODH; O-GlcNAcylation; PIK3CA mutation

摘要：Cancer cells acquire distinct metabolic and signaling dependencies driven by oncogenic mutations. Defining these mutation-specific liabilities can uncover therapeutic opportunities. Here, we identify dihydroorotate dehydrogenase (DHODH) as a selective metabolic dependency in PIK3CA-mutant colorectal cancer (CRC). DHODH sustains WDR77 O-GlcNAcylation and protein stability by promoting the generation of uridine diphosphate (UDP)-N-acetylglucosamine (UDP-GlcNAc), thereby maintaining PI3K-AKT signaling. Genetic or pharmacological inhibition of DHODH reduces WDR77 protein abundance, decreases phosphorylated AKT, and impairs cancer cell self-renewal and tumor initiation. Uridine supplementation restores WDR77 and AKT signaling, whereas O-GlcNAc transferase (OGT) depletion abrogates this rescue, establishing a UDP-dependent mechanism linking pyrimidine metabolism to signaling maintenance. Treatment with the DHODH inhibitor HL6 recapitulates the genetic phenotypes and suppresses tumor growth in xenograft, orthotopic, and patient-derived CRC models. This study demonstrates that the metabolic regulation of protein stability represents a critical mechanism underlying oncogene-specific dependencies in CRC.