IDO1 methylation by EZH2 confers resistance to its targeted therapy in colorectal cancer through tryptophan-kynurenine metabolic rewiring
Abstract
Deciphering cancer metabolic reprogramming mechanisms can identify new targets to potentiate EZH2 inhibitor efficacy. Using an in vivo genome-wide CRISPR loss-of-function screen in a CRC mouse model, we pinpointed IDO1 as a key mediator of EZH2 inhibitor resistance. EZH2 blockade remodeled CRC cell metabolism by upregulating IDO1 protein and hyperactivating the tryptophan-kynurenine pathway. Both genetic and pharmacological inhibition of IDO1 suppressed tumor growth and rescued EZH2 inhibitor resistance in vitro and in vivo . Mechanistically, EZH2 directly binds and methylates IDO1. Methylation of IDO1 facilitates IDO1 ubiquitination and subsequent degradation. Accordingly, EZH2 inhibition stabilizes IDO1, augments tryptophan-kynurenine metabolic flux, and ultimately confers therapeutic resistance. In summary, our study identifies IDO1 as a non-histone substrate of EZH2 methyltransferase activity and validates that disrupting IDO1-mediated tryptophan metabolism is a viable strategy to overcome EZH2 targeted therapy resistance in cancers.
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BibTeX
@article{tang2026ido1,
title = {{IDO1 methylation by EZH2 confers resistance to its targeted therapy in colorectal cancer through tryptophan-kynurenine metabolic rewiring}},
author = {Yuanjun Tang and Zhanya Huang and Yiting Jia and Yunyun Guo and Xuedi Cao and Renjing Jin and Qianqian Yin and Jiagui Song and Huiguang Chen and Xintong Zhang and Xin Zhou and Rui Cheng and Jianling Yang and Zhengyang Guo and Pengcheng Bu and Lixiang Xue},
journal = {Cell Reports},
year = {2026},
month = nov,
doi = {10.1016/j.celrep.2026.118237},
url = {https://linkinghub.elsevier.com/retrieve/pii/S2211124726013161},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - IDO1 methylation by EZH2 confers resistance to its targeted therapy in colorectal cancer through tryptophan-kynurenine metabolic rewiring
AU - Yuanjun Tang
AU - Zhanya Huang
AU - Yiting Jia
AU - Yunyun Guo
AU - Xuedi Cao
AU - Renjing Jin
AU - Qianqian Yin
AU - Jiagui Song
AU - Huiguang Chen
AU - Xintong Zhang
AU - Xin Zhou
AU - Rui Cheng
AU - Jianling Yang
AU - Zhengyang Guo
AU - Pengcheng Bu
AU - Lixiang Xue
PY - 2026
DA - 2026/11/01
JO - Cell Reports
DO - 10.1016/j.celrep.2026.118237
UR - https://linkinghub.elsevier.com/retrieve/pii/S2211124726013161
AB - Deciphering cancer metabolic reprogramming mechanisms can identify new targets to potentiate EZH2 inhibitor efficacy. Using an in vivo genome-wide CRISPR loss-of-function screen in a CRC mouse model, we pinpointed IDO1 as a key mediator of EZH2 inhibitor resistance. EZH2 blockade remodeled CRC cell metabolism by upregulating IDO1 protein and hyperactivating the tryptophan-kynurenine pathway. Both genetic and pharmacological inhibition of IDO1 suppressed tumor growth and rescued EZH2 inhibitor resistance in vitro and in vivo . Mechanistically, EZH2 directly binds and methylates IDO1. Methylation of IDO1 facilitates IDO1 ubiquitination and subsequent degradation. Accordingly, EZH2 inhibition stabilizes IDO1, augments tryptophan-kynurenine metabolic flux, and ultimately confers therapeutic resistance. In summary, our study identifies IDO1 as a non-histone substrate of EZH2 methyltransferase activity and validates that disrupting IDO1-mediated tryptophan metabolism is a viable strategy to overcome EZH2 targeted therapy resistance in cancers.
SN - 2211-1247
ER -