Acetylation is an important post-translational modification (PTM) that involves the addition of acetyl functional groups to proteins. This modification can affect protein activity and has wide ranging effects from loosening of chromatin structure for the facilitation of DNA replication and repair, to influencing the sub-cellular location of individual proteins. Importantly, the enzymes that control protein acetylation are attracting interest as targets for novel drugs to treat cancer and neurodegenerative disease. To support this approach, a better understanding of the distribution and role of this PTM in specific disease states is needed. In a study by Hu and colleagues, researchers examine acetylation in tissue samples collected from tumors from hepatocellular carcinoma patients and the matched adjacent noncancerous tissues. Like other PTMs, the pool of modified proteins and/or peptides can be small in comparison to the total proteome and enrichment methods can be beneficial. Hu and colleagues digested the samples and used half for proteome analysis, and then used immunoaffinity enrichment to isolates peptides containing acetyl-lysines from the other half of the sample. The resulting peptide pools were then analyzed by LC-MS/MS. This study explores the link between acetylation and metabolism in the tumor microenvironment and demonstrates the utility of global analysis tools like proteomics for studying complex disease states.
How was PEAKS used?
MS data was analysed using PEAKS Studio 8.5. Database searches were completed against a human database, with oxidation of methionine, deamidation of asparagine or glutamine, acetylation of lysine or the N-terminal residue as variable modifications. Data was exported from PEAKS and statistical analysis and bioinformatics were performed using the R environment (version 3.4.3) and DAVID Bioinformatics Resources 6.8.
Hu, Xiaowen, et al. “Disturbed Mitochondrial Acetylation in Accordance with the Availability of Acetyl Groups in Hepatocellular Carcinoma.” Mitochondrion, Elsevier BV, Aug. 2021. Crossref, doi:10.1016/j.mito.2021.08.004. PMID: 34375734.
As an essential post-translational modification, acetylation participates in various cellular processes and shows aberrances during tumorigenesis. Owing to its modification substrate, acetyl-CoA, acetylation is postulated as a depot for acetyl groups and evolve to build a connection between epigenetics and metabolism. Here we depict a distinct acetylome atlas of hepatocellular carcinoma from the perspectives of both protein acetylation and acetyl-CoA metabolism. We found that tumor acetylome demonstrated a compartment-dependent alteration that the acetylation level of mitochondrial proteins tended to be decreased while nuclear proteins were highly acetylated. In addition, elevated expression of ATP-citrate synthase (ACLY) was observed in tumors, which would facilitate histone acetylation by transporting mitochondrial acetyl coenzyme A to the nucleus. A hypothetical model of the oncogenic acetylome was proposed that growing demands for histone acetylation in tumor cells would drive the relocalization of acetyl-CoA to the nucleus, which may contribute to the global deacetylation of mitochondrial proteins to support the nuclear acetyl-CoA pool in an ACLY-dependent manner. Our findings are thought-provoking on the potential linkage between epigenetics and metabolism in the progression of tumorigenesis.