Lysine Acetylome Study of Human Hepatocellular Carcinoma Tissues for Biomarkers and Therapeutic Targets Discovery

Abstract

Lysine acetylation is a vital post-translational modification (PTM) of proteins, which plays an important role in cancer development. In healthy human liver tissues, multiple non-histone proteins were identified with acetylation modification, however, the role of acetylated proteins in hepatocellular carcinoma (HCC) development remains largely unknown. Here we performed a quantitative acetylome study of tumor and normal liver tissues from HCC patients. Overall, 598 lysine acetylation sites in 325 proteins were quantified, and almost 59% of their acetylation levels were significantly changed. The differentially acetylated proteins mainly consisted of non-histone proteins located in mitochondria and cytoplasm, which accounted for 42% and 24%, respectively. Bioinformatics analysis showed that differentially acetylated proteins were enriched in metabolism, oxidative stress, and signal transduction processes. In tumor tissues, 278 lysine sites in 189 proteins showed decreased acetylation levels, which occupied 98% of differentially acetylated proteins. Moreover, we collected twenty pairs of tumor and normal liver tissues from HCC male patients, and found that expression levels of SIRT1 (p = 0.002), SIRT2 (p = 0.01), and SIRT4 (p = 0.045) were significantly up-regulated in tumor tissues. Over-expression of possibly accounted for the widespread deacetylation of non-histone proteins identified in HCC tumor tissues, which could serve as promising predictors of HCC. Taken together, our work illustrates abundant differentially acetylated proteins in HCC tumor tissues, and offered insights into the role of lysine acetylation in HCC development. It provided potential biomarker and drug target candidates for clinical HCC diagnosis and treatment.

Quantitative acetylome analysis reveals histone modifications that may predict prognosis in hepatitis B‐related hepatocellular carcinoma

“…55 Thus, the highly expressed and acetylated CPS1 in liver cells may be involved in development of liver cancer. HADHA is a mitochondrial trifunctional enzyme specifically involved in the last three of the four reactions of long-chain fatty acids beta-oxidation pathway, [56][57][58] and the acetylation levels of the K60, K129, and K569 of HDAHA were also downregulated in tumor tissues, 7 which is consistent with our results (Table S6). Moreover, several novel Kac sites were identified in this study ( Figure 7D).…”

“…6 However, the acetylome atlases in HCC, paracancerous, and normal liver tissues are unknown, which hampers the understanding of acetylation role in HCC pathology. Recently researches reported a tandem mass tag (TMT)labeling acetylome for human HCC and normal tissues, 7 but the number of Kac proteins and sites was lower than ours. Acetyl-CoA is the key central metabolite and the donor of the acetyl group in protein acetylation.…”

“…In their work, Zhao et al. also found that GLUD1 was acetylated at K191, K390, K457, K489, and K527 and all the acetylation levels were downregulated in tumor tissues, 7 which is consistent with our data (Table S6) ADH1B is a disease‐associated protein of alcohol dependence and fetal alcohol syndrome, 61 which catalyzes the NAD‐dependent oxidation of all‐trans‐retinol and its derivatives involved in retinoid metabolism 58,62 . These results indicate that this multiacetylated protein may be involved in the response to proliferation, migration, and invasion in HCC.…”

Identification of NAA40 as a Potential Prognostic Marker for Aggressive Liver Cancer Subtypes

“…Acetyltransferases are enzymes that transfer acetyl groups to proteins, with this post-translational modification (PTM) potentially affecting the target proteins in multiple ways. The involvement of lysine acetyltransferases, which acetylate the lysine residue of histone and non-histone proteins, in LIHC has been extensively studied and is well established (12)(13)(14). Another category of protein acetyltransferases are the Nterminal acetyltransferases (NATs), that specifically modify the N-terminal a-amino group of proteins or polypeptides (15).…”

In-depth Profiling and Quantification of the Lysine Acetylome in Hepatocellular Carcinoma with a Trapped Ion Mobility Mass Spectrometer

“…SIRT2 has been reported to modulate the acetylation and activities of several enzymes involved in glycolysis, for example, phosphoglycerate mutase 1, and enzymes from the pentose phosphate pathway, for example, glucose-6-phosphate dehydrogenase ( 14 ). With the advance in modern mass spectrometry, more and more K-acetylation sites are being characterized ( 11 , 13 , 26 ), however, how majority of these sites are regulated and more importantly how they are involved in diseases remain largely unclear.…”