Authors
Jun Liang, Xi Liu, Ziyun Ni, Sen Zhang, Xiangli He, Lili Wang, Yukun Huang, Zhaomin Xu, Zhongyu Xu, Jiayi Qian, Lixue Lu, Naijipu Abuduaini, Jing Tian, Minghua Zeng, Qi Wang, Jing Sun, Qiong Xie, Yonghui Wang, Weiqiang Lu, Bo Feng, Bo Han, Jin Huang
Published in
Cell reports. Volume 45. Issue 8. Pages 117719. Jul 24, 2026. Epub Jul 24, 2026.
Abstract
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.
PMID:
42497063
Bibliographic data and abstract were imported from PubMed on 25 Jul 2026.
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