组蛋白甲基转移酶和去甲基化酶介导的异常表观遗传事件导致结直肠癌（CRC）的恶性进展。然而，组蛋白去甲基化酶普遍转录的四联体重复蛋白在X染色体上（UTX）在CRC中的作用仍不明确。本研究使用UTX条件敲除小鼠和UTX沉默的MC38细胞研究UTX在肿瘤发生和CRC发展中的功能。我们进行飞行时间质谱法以阐明UTX在重塑CRC免疫微环境中的功能作用。为了研究髓源性抑制细胞（MDSCs）和CRC之间的代谢相互作用，我们分析代谢组学数据以识别被UTX缺陷癌细胞分泌并被MDSCs吸收的代谢物。我们揭示了MDSC和UTX缺陷CRC之间的酪氨酸介导的代谢共生关系。在CRC中丢失UTX导致苯丙氨酸羟化酶的甲基化，防止其降解，并随之增加酪氨酸的合成和分泌。MDSC吸收的酪氨酸由羟基苯基丙酮酸双加氧酶（HPD）代谢为同黑色素酸（HGA）。HGA经由卡邦化Cys 176修饰PIAS3，并减轻PIAS3对STAT5转录活性的抑制作用。这反过来促进了MDSC的存活和积累，使CRC细胞获得侵袭和转移特性。综上所述，这些发现强调了HPD作为代谢检查点以限制免疫抑制的MDSCs，并抵抗UTX缺陷CRC的恶性进展。版权所有©2023 AGA Institute。由Elsevier Inc.出版。保留所有权利。

Aberrant epigenetic events mediated by histone methyltransferases and demethylases contributes to malignant progression of colorectal cancer (CRC). However, the role of the histone demethylase ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX) in CRC remains poorly understood.UTX conditional knock-out mice and UTX-silenced MC38 cells were used to investigate UTX function in tumorigenesis and development of CRC. We performed Time of Flight Mass Cytometry to clarify the functional role of UTX in remodeling immune microenvironment of CRC. To investigate metabolic interaction between myeloid-derived suppressor cells (MDSCs) and CRC, we analyzed metabolomics data to identify metabolites secreted by UTX-deficient cancer cells and taken up by MDSCs.We unraveled a tyrosine-mediated metabolic symbiosis between MDSC and UTX-deficient CRC. Loss of UTX in CRC resulted in methylation of phenylalanine hydroxylase, preventing its degradation and subsequently increasing tyrosine synthesis and secretion. Tyrosine taken up by MDSCs was metabolized to homogentisic acid (HGA) by hydroxyphenylpyruvate dioxygenase (HPD). HGA modified PIAS3 via carbonylation of Cys 176, and relieved the inhibitory effect of PIAS3 on STAT5 transcriptional activity. This in turn, promoted MDSCs survival and accumulation, enabling CRC cells to acquire invasive and metastatic traits.Collectively, these findings highlight HPD as a metabolic checkpoint to restrict immunosuppressive MDSCs and to counteract malignant progression of UTX-deficient CRC.Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.