Adipocytic Glutamine Synthetase Upregulation via Altered Histone Methylation Promotes 5FU Chemoresistance in Peritoneal Carcinomatosis of Colorectal Cancer

• DOI: 10.3389/fonc.2021.748730
• Publication Date: 2021-10-13T17:45:49Z
• Authors: Xuan Zhang; Qing Li; Aibei Du; Yifei Li; Qing Shi; Yanrong Chen; Yang Zhao; Bin Wang; Feng Pan
• Keywords: Demethylase

The development of resistance to 5-fluorouracil (5FU) chemotherapy is a major handicap for sustained effective treatment in peritoneal carcinomatosis (PC) colorectal cancer (CRC). Metabolic reprogramming adipocytes, component the tumor microenvironment and main composition peritoneum, plays significant role drug PC, with mechanisms being not fully understood. By performing metabolomics analysis, we identified glutamine (Gln), an important amino acid, inducing 5FU-triggered suppression CRC-PC through activating mTOR pathway. Noteworthily, genetic overexpression synthetase (GS) adipocytes increased chemoresistance 5FU vitro vivo while this effect was reversed by pharmacological blockage GS. Next, showed that methionine metabolism were enhanced acid omitted from GS transgenic (TgGS) mice, increasing intracellular levels S-carboxymethy-L-cys. Moreover, loss dimethylation at lysine 4 histone H3 (H3k4me2) found vitro, which may lead expression Furthermore, biochemical inhibition specific demethylase 1 (LSD1) restored H3k4me2, thereby reducing GS-induced 5FU. Our findings indicate upregulation-induced excessive Gln via altered methylation potential mediator patients CRC-PC.