A Study On Metabolic Reprogramming And Its Regulation On Acetylome In Digestive System Tumors

Mutations on oncogenes or tumor suppressor genes confer sustaining proliferation on tumor cells.To survive the drastic alterations of both the internal oncogenic signaling and the external availability of nutrients and oxygen,cancer cells evolve the characterized metabolism called metabolism reprogramming,which is one of the hallmarks of cancer.To gain sufficient growth advantages,tumor cells change both the acquisition and the utilization of nutrients.As a versatile production line that generates metabolic intermediates for numerous biosynthetic processes,glycolysis is highly activated in cancer.The disturbance of metabolites would reversely impact the metabolic network.Acetyl-Co A is a central intermediate in cellular metabolism.Elaborate coordination occurs between energy metabolism and material metabolism by regulation of the production and the consumption of acetyl-Co A.In addition,acetyl-Co A serves as the donor of the acetyl group in protein acetylation,which builds a crosstalk between the post-translational modifications(PTMs)and cellular metabolism.The fluctuation of acetylCo A storage caused by metabolism reprogramming would subsequently contribute to the perturbation of protein acetylation,which affects both the transcriptional regulation and enzymatic activities.Researches on the characteristics of metabolic dysfunction and acetylation regulation would help depict the crosstalk between metabolic networks and epigenetics and elucidate their roles in oncogenesis.Mass spectrometry(MS)-based proteomics is highly efficient in protein identification and quantification,which shows a good performance in sensitivity,accuracy and throughput.MS platform could not only analyze the protein components of cell lysates and identify PTMs when combined with specific immunoaffinity enrichments.Recent years,numerous breakthroughs on the identification of PTMs have taken place via the applications of MS-based proteomics,which has expanded the knowledge of various PTMs to a certain extent.In this study,we performed a targeted quantitative proteomics on the glucose metabolism relevant proteins in 50 pairs of colorectal carcinoma(CRC)tumor tissues and their adjacent non-cancerous tissues using the multiple reaction monitoring technique.The protein expression levels demonstrated that glycolysis was highly activated in CRC,which is consistent with the aerobic glycolysis described in the Warburg effect.However,it seemed that TCA cycle showed no response to the activation of glycolysis,of which the enzymes exhibited no significant differences between tumors and normal tissues.In addition,we found that the pentose phosphate pathway was also promoted in CRC tumors.These results suggest that glycolysis and the pentose phosphate pathway are highly motorized in CRC to meet the growing demands of building blocks for biosynthesis.The targeted proteomic analysis has brought us an initial understanding on the metabolic dysfunction.To gain comprehensive scenarios on metabolic networks,we subsequently performed whole proteomic screenings on hepatocellular carcinomas.Systematic analyses focused on its production and the fate of the central intermediate acetyl-Co A were carried out.The altered expression levels of relevant proteins demonstrated that catabolic metabolism occurred in mitochondria seemed to be inhibited,suggesting that the production of acetyl-Co A was blocked.However,the anabolic metabolism in the cytosol were promoted,especially the fatty acid biosynthesis.In addition,citrate-malate shuttle,the route by which activated in HCC tumors.These results suggested that despite its deficiency in production,mass acetyl-Co A were moved out of mitochondria to support the great demands of biosynthesis occurred in cytosol.The proteomic research hinted us that the homeostasis of acetyl-Co A metabolism was disequilibrated in HCC.Given the potential effects of the acetyl-Co A level on protein acetylations,we subsequently performed a research on the acetylome in HCC.We found that protein acetylations were experiencing disturbance in HCC tumors,and the acetylome presented a global regulation in a cellular compartment-characterized manner.In HCC tumor tissues,mitochondrial proteins seemed to experience pervasive deacetylation,while nuclear proteins tended to be actively acetylated.Given the observations in the proteomic study that both the production of acetyl-Co A and its fate were perturbed,we suppose that the compartment-characterized regulation of HCC acetylome may be a compromise faced with the dual pressures of acetyl-Co A exhaustion induced by the growing transcriptional needs and the biosynthesis.Great demands in the nuclear-cytosolic pool drive the translocation of acetyl-Co A out of the mitochondria through ACLYdependent migration,resulting in the universal deacetylation of mitochondrial proteins to support the acetyl-Co A pool upon the its deficiency in production.Compared with the enzymatic site-specific regulation,the global regulation of mitochondrial protein acetylations emerged like a general utilization upon acetyl-Co A shortage.The hypothetical model of the acetylomic regulation provides new insights into the crosstalk and the potential regulatory mechanism between epigenetic regulation and cellular metabolism during tumorigenesis.Our study investigated the characteristics of metabolic dysfunction and acetylomic regulation in CRC and HCC,which elucidated the coordination and interaction between the metabolism and epigenetics in these two major categories of digestive system tumors.Intense efforts on their relationship would enlighten the investigations on tumorigenesis mechanism and clinical intervention.