GSE167474
Histone N-terminal acetyltransferase NAA40 links one-carbon metabolism to chemoresistance
Epigenetic regulation and metabolism are highly interconnected, but it remains unclear if this interplay is harnessed by cancer cells to evade chemotherapy. Here, using transcriptomic and metabolomic analysis in colorectal cancer cells, we demonstrate that N-alpha-acetyltransferase 40 (NAA40), which catalyzes N-terminal acetylation of histones H4 and H2A, controls the expression of key one-carbon metabolic enzymes and the abundance of corresponding metabolites. Specifically, we show that NAA40 deficiency induces the methionine cycle thereby increasing global histone methylation and attenuates transcription of the metabolic gene thymidylate synthase (TYMS) whose product is targeted by 5-fluorouracil (5-FU). Accordingly, we show that NAA40 activates TYMS by preventing deposition of H2A/H4S1ph at the nuclear periphery and confers resistance against the antimetabolite 5-FU in vitro and in xenografts. Consistently, in primary tumours NAA40 expression associates with TYMS levels and poorer 5-FU response. Overall these findings define a novel role for NAA40 in controlling cellular metabolism and chemoresistance. Overall design: Function of NAA40 in metabolism and chemoresistance