Stratification of Hepatocellular Carcinoma Patients Based on Acetate Utilization

• Published in: Cell reports (Cambridge) 2015-12, Vol.13 (9), p.2014-2026
• Main Authors: Björnson, Elias, Mukhopadhyay, Bani, Asplund, Anna, Pristovsek, Nusa, Cinar, Resat, Romeo, Stefano, Uhlen, Mathias, Kunos, George, Nielsen, Jens, Mardinoglu, Adil
• Format: Article
• Language: English
• Subjects: acetate; Acetate-CoA Ligase - genetics; Acetate-CoA Ligase - metabolism; Acetates - metabolism; ACSS1; ACSS2; Aged; Algorithms; Animals; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell and Molecular Biology; Cell Line, Tumor; Cell- och molekylärbiologi; Fatty Acids - biosynthesis; Female; genome-scale metabolic models; hepatocellular carcinoma; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Male; Mice; Middle Aged; Mitochondria - metabolism; proteome; RNA, Messenger - metabolism; transcriptome
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2015.10.045

Hepatocellular carcinoma (HCC) is a deadly form of liver cancer that is increasingly prevalent. We analyzed global gene expression profiling of 361 HCC tumors and 49 adjacent noncancerous liver samples by means of combinatorial network-based analysis. We investigated the correlation between transcriptome and proteome of HCC and reconstructed a functional genome-scale metabolic model (GEM) for HCC. We identified fundamental metabolic processes required for cell proliferation using the network centric view provided by the GEM. Our analysis revealed tight regulation of fatty acid biosynthesis (FAB) and highly significant deregulation of fatty acid oxidation in HCC. We predicted mitochondrial acetate as an emerging substrate for FAB through upregulation of mitochondrial acetyl-CoA synthetase (ACSS1) in HCC. We analyzed heterogeneous expression of ACSS1 and ACSS2 between HCC patients stratified by high and low ACSS1 and ACSS2 expression and revealed that ACSS1 is associated with tumor growth and malignancy under hypoxic conditions in human HCC. [Display omitted] •Reconstruction of a genome-scale metabolic model for HCC tumors•Revealing metabolic alterations in HCC•Analysis of the heterogeneous expression of ACSS1 and ACSS2 between HCC tumors•Induction of ACSS1 in murine and human HCC samples under hypoxic conditions Stratification of HCC patients is vital for the development of effective treatment strategies. Björnson et al. stratify HCC patients based on acetate utilization and find that mitochondrial acetate is a metabolic fuel under hypoxic conditions. This is mediated by ACSS1, which may be a potential therapeutic target for treatment of HCC.