Histone N-terminal acetyltransferase NAA40 links one-carbon metabolism to chemoresistance
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ABSTRACT:
PROVIDER: PRJNA704699 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13780200.fastq.gz | Fastqsanger.gz | |||
| SRR13780201.fastq.gz | Fastqsanger.gz | |||
| SRR13780202.fastq.gz | Fastqsanger.gz | |||
| SRR13780203.fastq.gz | Fastqsanger.gz | |||
| SRR13780204.fastq.gz | Fastqsanger.gz |
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Project description: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.
2021-11-15 | GSE167474 | GEO
Project description: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.
| S-EPMC8782725 | biostudies-literature
Project description:Search for genes differently expressed when we inhibit NatB N-terminal acetyltransferase. We compare gene expression after inhibiting hNAT5 expression in Hela cells with specific siRNAs expressed with adenoviruses. Keywords: gene expression comparison
2008-03-12 | GSE10779 | GEO
Project description:Search for genes differently expressed when we inhibit NatB N-terminal acetyltransferase. We compare gene expression after inhibiting hNAT5 expression in Hela cells with specific siRNAs expressed with adenoviruses. Experiment Overall Design: We analyzed duplicate samples and we used as controls Hela cells and Hela cells that express a siRNA that doesn't inhibit any gene expression. Experiment Overall Design: The N-terminal acetyltransferase NatB, composed in Saccharomyces cerevisiae by the Nat3p and Mdm20p subunits, is an important factor for yeast growth and resistance to several stress agents. However, the expression and functional role of the mammalian counterpart has not yet been analysed. Here, we report the identification of Nat3p human homologue (hNAT5/hNAT3) and the characterization of its biological function. We found that hNAT5/hNAT3 silencing in HeLa cells results in inhibition of cell proliferation and increased sensitivity to the proapoptotic agent MG132. Moreover, inhibition of hNAT5/hNAT3 expression induces p53 activation and upregulation of the antiproliferative protein p21(WAF1/CIP1). The changes of the cellular transcriptome after hNAT5/hNAT3 knockdown confirmed the involvement of this protein in cell growth and survival processes. Among the genes differentially expressed we observed upregulation of several p53-dependent antiproliferative and proapoptotic genes. In the c-myc transgenic mice which is a model of inducible hepatocarcinoma we found that hNAT5/hNAT3 was upregulated when the tumor was induced. In accordance with this observation we noticed increased hNAT5/hNAT3 protein level in neoplastic versus non-neoplastic tissue in a high proportion of patients with hepatocellular carcinoma. Consequently, our results suggest that the expression of the protein hNAT5/hNAT3 is required for cellular proliferation and tumor growth.
2008-04-05 | E-GEOD-10779 | biostudies-arrayexpress
Project description:Acetylcytidine modification of DDX41 and ZNF746 by N-acetyltransferase 10 contributes to chemoresistance of melanoma
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Project description:N-acetyltransferase 10 drives cisplatin chemoresistance by enhancing ac4C-associated DNA repair in bladder cancer
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Project description:Both, acetylation of histones and of histone variant H2A.Z are conserved features of eukaryotic transcription start sites (TSSs) and both features appear to be critical for correct transcription initiation. However, complex patterns of transcriptional regulation have complicated the establishment of functional links between histone acetylation, H2A.Z deposition and their importance in transcription regulation. To elucidate these links, we took advantage of the unusual genome organization in Trypanosoma brucei, a highly divergent eukaryote. In T. brucei genes are organized in long polycistronic transcription units, drastically reducing the sites of transcription initiation. Employing a highly sensitive and quantitative mass-spectrometry-based approach, we quantified the genome-wide histone acetylation and methylation pattern and identified various acetyl and methyl marks exclusively enriched at TSSs In addition, we show that deletion of histone acetyltransferase 2 results in a loss of H4 acetylation at TSSs, a loss of H2A.Z deposition at TSSs and a shift in the sites of transcription initiation. Combined, our findings demonstrate an evolutionary conserved link between histone H4 acetylation, H2A.Z deposition and RNA transcription initiation.
2020-03-24 | PXD014452 | Pride
Project description:The euchromatin histone methyltransferase 2 (EHMT2, aka G9a) methylates histone H3K9 to repress gene expression, but it also acts as a coactivator for some nuclear receptors. The molecular mechanisms underlying this activation remain elusive. Here we show that G9a functions as a bona fide coactivator of the endogenous estrogen receptor α (ERα) in breast cancer cells in a histone methylation-independent manner. G9a dimethylates ERα protein at lysine 235 both in vitro and in cells. Dimethylation of ERαK235 (ERαK235me2) is recognized by the Tudor domain of PHF20, which in turn recruits the MOF histone acetyltransferase (HAT) complex to ERα target gene promoters to deposit histone H4K16 acetylation promoting active transcription. Together, our in vitro and in vivo data establish the molecular mechanism by which G9a functions as an ERα coactivator. Along with the PHF20/MOF complex, G9a links the crosstalk between ERα methylation and histone acetylation governing the epigenetic regulation of hormonal gene expression.
2016-04-07 | GSE76507 | GEO
Project description:Protein N-terminal (Nt) acetylation is one of the most abundant modifications in eukaryotes, covering ~50-80 % of the proteome, depending on species. Cells with defective Nt-acetylation display a wide array of phenotypes such as impaired growth, mating defects and increased stress sensitivity. However, the pleiotropic nature of these effects has hampered our understanding of the functional impact of protein Nt-acetylation. The main enzyme responsible for Nt-acetylation throughout the eukaryotic kingdom is the N-terminal acetyltransferase NatA. Here we employed a multi-dimensional proteomics approach to analyze Saccharomyces cerevisiae lacking NatA activity, which caused global proteome remodeling. Pulsed-SILAC experiments revealed that NatA-deficient strains consistently increased degradation of ribosomal proteins compared to wild type. Explaining this phenomenon, thermal proteome profiling uncovered decreased thermostability of ribosomes in NatA-knockouts. Our data are in agreement with a role for Nt-acetylation in promoting stability for parts of the proteome by enhancing the avidity of protein-protein interactions and folding.
2023-10-24 | PXD037510 | Pride
Project description:Quantitative study of the N-terminal acetylome variations in Arabidopsis thaliana, looking at the effect of a N-acetyltransferase KO.
2020-07-13 | PXD016496 | Pride