Abstract
Aberrant function of epigenetic modifiers plays an important role not only in the progression of cancer but also the development of drug resistance. N-alpha-acetyltransferase 40 (NAA40) is a highly specific epigenetic enzyme catalyzing the transfer of an acetyl moiety at the N-terminal end of histones H4 and H2A. Recent studies have illustrated the essential oncogenic role of NAA40 in various cancer types but its role in chemoresistance remains unclear. Here, using transcriptomic followed by metabolomic analysis in colorectal cancer (CRC) cells, we demonstrate that NAA40 controls key one-carbon metabolic genes and corresponding metabolites. In particular, through its acetyltransferase activity NAA40 regulates the methionine cycle thereby affecting global histone methylation and CRC cell survival. Importantly, NAA40-mediated metabolic rewiring promotes resistance of CRC cells to antimetabolite chemotherapy in vitro and in xenograft models. Specifically, NAA40 stimulates transcription of the one-carbon metabolic gene thymidylate synthase (TYMS), whose product is targeted by 5-fluorouracil (5-FU) and accordingly in primary CRC tumours NAA40 expression associates with TYMS levels and poorer 5-FU response. Mechanistically, NAA40 activates TYMS by preventing enrichment of repressive H2A/H4S1ph at the nuclear periphery. Overall, these findings define a novel regulatory link between epigenetics and cellular metabolism mediated by NAA40, which is harnessed by cancer cells to evade chemotherapy.
Highlights
Histone acetyltransferases (HATs) play a pivotal role in the regulation of gene transcription and chromatin structure by transferring an acetyl group from acetyl-CoA to either the side chain of internal lysine residues or the N-terminal tip of histone proteins [1]
Given that we identified thymidylate synthase (TYMS) to be significantly downregulated upon N-alpha-acetyltransferase 40 (NAA40)-knockdown (Fig. 1A, C) and the fact that Cancer Dependency Map (DepMap) data analysis shows significant positive correlation (r = 0.43, p < 0.001) between NAA40 and TYMS expression in 70 different colorectal cancer (CRC) cell lines (Supplementary Fig. S6A), we speculated that NAA40 could be a novel regulator of TYMS affecting the response of CRC cells to 5-FU
We have focused our studies on deciphering the molecular role of NAA40 in colorectal cancer in which it was previously implicated [5] and we have established a new function for this enzyme in bridging epigenetic regulation and metabolism that is exploited by cancer cells to counteract anti-metabolite drug therapy
Summary
Histone acetyltransferases (HATs) play a pivotal role in the regulation of gene transcription and chromatin structure by transferring an acetyl group from acetyl-CoA to either the side chain of internal lysine residues or the N-terminal tip of histone proteins [1]. Accumulating evidence derived from in vitro, in vivo and clinical studies by our group and others implicate NAA40 and its associated histone N-terminal acetylation in tumour growth and metastasis of different cancers including lung, liver and colorectal cancer (CRC) [5,6,7]. We found that NAA40 regulates the expression of genes encoding vital enzymes involved in one-carbon (1 C) metabolic network thereby influencing the abundance of intermediary metabolites of this pathway including S-adenosyl methionine (SAM) and uridine monophosphate (UMP). NAA40-mediated activation of the 1C-metabolic gene TYMS confers 5-FU resistance to CRC cells and in human colorectal tumours NAA40 expression positively correlates with TYMS levels and worse response of.
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