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Acetylomics data of the Anti-Proliferative Activity of Safranal on Triple-Negative Breast Cancer Cell

ABSTRACT: We conducted a combining isobaric tag-based TMT labeling followed by enrichment of lysine acetylated peptides by Acetyl-Lysine Immunoprecipitation (IP) method as Acetylomics study on MDA-MB-231 treated with safranal.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

DISEASE(S): Breast Cancer

SUBMITTER: Mahshid Zarrineh

LAB HEAD: Martin Røssel Larsen

PROVIDER: PXD036333 | Pride | 2022-08-30

REPOSITORIES: Pride

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Project description:Alcohol consumption induces hepatocyte damage through complex processes involving oxidative stress and disrupted metabolism. Combined, these factors alter proteomic and epigenetic marks providing a critical opportunity to identify therapeutic targets. Indeed, alcohol-induced protein acetylation is a key post-translational modification (PTM) that regulates hepatic metabolism and is associated with the pathogenesis of alcohol-associated liver disease (ALD). Interestingly, recent evidence suggests lysine acetylation occurs when a proximal cysteine residue is within ~15 Å of a lysine residue, referred to as a cysteine-lysine (Cys-Lys) pair. Here, acetylation can occur through the transfer of an acetyl moiety via an S à N acetyl transfer reaction. Alcohol-mediated hepatic redox stress is known to occur coincident with lysine acetylation, but the biochemical mechanisms related to cysteine and lysine crosstalk within ALD remain unexplored. A chronic murine model of ALD was employed to quantify hepatic cysteine redox and lysine acetylation, revealing that alcohol metabolism significantly reduced the cysteine proteome and increased protein acetylation. Interrogating both cysteine redox and lysine acetylation datasets, 1,281 proteins were mapped by AlphaFold2 to quantify distances between 557,815 cysteine and lysine residues. This process identified 388,698 Cys-Lys pairs that were further used to evaluate thiol redox signaling. Our analysis reveals that alcohol metabolism induces redox changes and acetylation selectively on proximal Cys-Lys pairs with an odds ratio of 1.89 (p< 0.0001). We also identified key redox signaling hubs embedded in metabolic pathways associated with ALD, including lipid metabolism, the TCA cycle, and the electron transport chain. Specific protein targets embedded across these pathways include Echs1, Glrx5, Decr2, and Adh1, among many others. Interestingly, these proximal Cys-Lys exist as four major protein motifs represented by the number of Cys and Lys residues that are pairing (Cysx-Lysx). These motifs include Cys1:Lys1, Cysx:Lys1, Cys1:Lysx and Cysx:Lysx each with a unique microenvironment likely indicative of the mode of enzymatic regulation occurring. The motifs are composed of functionally relevant amino acids altered within ALD, identifying sites of therapeutic potential. Furthermore, these unique Cys-Lys redox signatures are translationally relevant as revealed by orthologous comparison with severe alcohol-associated hepatitis (SAH) explants, revealing numerous pathogenic thiol redox signals in these patients.

Project description:Acetylation at lysine residue in a protein mediates multiple cellular biological processes, including tumorigenesis. This study aimed to investigate the acetylated protein profile alterations and acetylation-mediated molecular pathway changes in human nonfunctional pituitary neuroendocrine tumors (NF-PitNETs). The anti-acetyl antibody-based label-free quantitative proteomics was used to analyze the acetylomes between NF-PitNETs (n = 4) and control pituitaries (n = 4). A total of 296 acetylated proteins with 517 acetylation sites was identified, and the majority of which were significantly down-acetylated in NF-PitNETs (p<0.05 or only be quantified in NF-PitNETs/controls). These acetylated proteins widely functioned in cellular biological processes and signaling pathways, including metabolism, translation, cell adhesion, and oxidative stress. The randomly selected acetylated phosphoglycerate kinase 1 (PGK1), which is involved in glycolysis and amino acid biosynthesis, was further confirmed with immunoprecipitation and western blot in NF-PitNETs and control pituitaries. Among these acetylated proteins, 15 lysine residues within 14 proteins were down-acetylated and simultaneously up-ubiquitinated in NF-PitNETs to demonstrate a direct competition relationship between acetylation and ubiquitination. Moreover, the potential effect of protein acetylation alterations on NF-PitNETs invasiveness was investigated. Overlapping analysis between acetylomics data in NF-PitNETs and transcriptomics data in invasive NF-PitNETs identified 26 overlapped molecules. These overlapped molecules were mainly involved in metabolism-associated pathways, which means that acetylation-mediated metabolic reprogramming might be the molecular mechanism to affect NF-PitNET invasiveness. This study provided the first acetylomic profiling and acetylation-mediated molecular pathways in human NF-PitNETs, and offered new clues to elucidate the biological functions of protein acetylation in NF-PitNETs and discover novel biomarkers for early diagnosis and targeted therapy of NF-PitNETs.

			Action	DRS
	LUM_05061_Mahshid.mzML	Mzml
	LUM_05061_Mahshid.raw	Raw
	Mashid_acetylated.mzML	Mzml
	Mashid_acetylated.mzid.gz	Mzid
	checksum.txt	Txt

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Acetylomics data of the Anti-Proliferative Activity of Safranal on Triple-Negative Breast Cancer Cell

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