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