LAUSR

BACKGROUND & AIMS 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. METHODS 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. RESULTS 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. CONCLUSIONS Collectively, these findings highlight HPD as a metabolic checkpoint to restrict immunosuppressive MDSCs and to counteract malignant progression of UTX-deficient CRC.