Crosstalk among proteome, acetylome and succinylome in colon cancer HCT116 cell treated with sodium dichloroacetate

Abstract

Protein lysine acetylation and succinylation play important regulatory roles in cells, both of which or each other has a close relationship. Dichloroacetate (DCA), a well-known pyruvate dehydrogenase kinase (PDK) inhibitor, has the potential to be used as anti-cancer drugs for several tumors including colorectal cancer. However, little is known about the potential mechanism of DCA-based cancer therapy by protein posttranslational modifications (PTM) including global proteome, acetylome and succinylome. Here the combinations with stable isotope labeling (SILAC), antibody affinity enrichment and high resolution LC-MS/MS analysis were performed in human colon cancer HCT116 cells. The quantifiable proteome was annotated using bioinformatics. In total, 4,518 proteins, 1,436 acetylation sites, and 671 succinylation sites were quantified, respectively to DCA treatment. Among the quantified acetylated sites, 158 were with increased level (quantification ratio >1.5) and 145 with decreased level (quantification ratio <0.67). Meanwhile, 179 up-regulated and 114 down-regulated succinylated sites were identified. The bioinformatics analyses initially showed acetylation and succinylation were involved in a wide range of cellular functions upon DCA-based anti-cancer effects. Notably, protein-protein interaction network analyses demonstrated widespread interactions modulated by protein acetylation and succinylation. Taken together, this study may shed a light on understanding the mechanism of DCA-based cancer treatment.

Pyruvate dehydrogenase kinase 1 interferes with glucose metabolism reprogramming and mitochondrial quality control to aggravate stress damage in cancer

“…The PDK1/PDH loop has an important role in regulating glycolysis and mitochondrial oxidative phosphorylation energy metabolism [31]. Therefore, restoration of mitochondrial oxidative phosphorylation by PDK1 inhibition becomes a potential new therapeutic target for tumor treatment [31][32][33]. However, the mechanisms of how changes in metabolic patterns affect tumor cell mitochondrial function are unclear.…”

Role of the Pyruvate Dehydrogenase Complex in Metabolic Remodeling: Differential Pyruvate Dehydrogenase Complex Functions in Metabolism

“…They are separately dependent on the level of acetyl-CoA and succinyl-CoA, and both can be reversed by members of the SIRT family [ 14 ]. Large-scale quantitative analysis of the global proteome, acetylome, and succinylome using high sensitivity mass spectrometry and bioinformatics demonstrates that both acetylation and succinylation affect specific enzymes of central carbon metabolism including PDH, mediated by the anti-tumoral effect of DCA [ 15 ]. Based on the growing data set of acetylation and succinylation in various proteins, modification of residues on PDC should be assessed to show their significance in the overall function.…”

The Effects of Storage on Platelet Proteome Assessed by Protein Expression Changes and Lysine Modification Changes Using Tmt Isobaric Labeling

“…The TMT-labeled LC-MS/MS combined with pre-fractionation by HPLC allows for comprehensive proteome pro ling with deep coverage [49,50]. Combined with acetylated and succinylatedpeptide enrichment methods [51][52][53], this strategy was able to determine the level of global proteomic changes, as well as expression changes of acetylome and succinylome, simultaneously [54]. To analyze the dynamics and regulations of plateletsstored for 1, 3, 5, 7 days, we applied the strategy described above to achieve global proteome, acetylome, and succinylome for clinical platelets at 4 time points, respectively.…”