Chanyanuch Nakapakorn

 Introduction: Hepatocellular carcinoma (HCC) is ranked 3^rd in cancer mortality in developed countries with poor prognosis.¹ Higher risk of developing HCC is associated with hepatitis B or C, alcohol-related liver damage, metabolic diseases, and mutations.^1,8 Commonly, patients are diagnosed by biopsy but are often asymptomatic resulting in late diagnosis.^1,6 Altered levels of bacterial metabolites have been associated with HCC progression. Gut microbiota produces acetate.⁹ Therefore, microbiota dysbiosis can increase acetate levels and may be implicated in cancer ability to meet high energy demand. Uptake of acetate is increased in HCC during hypoxia and co-relates with cancer cell survival. Thus, understanding HCC metabolism can help us identify novel therapeutic targets, so the aim of this review is to give an overview of recent progress in HCC metabolic alterations caused by microbiota-derived acetate. Methods: Acetate treated HCC cells were analyzed by western blot for histone acetylation and qPCR of metabolic genes.² Kaplan-Meier Analysis of data from The Cancer Genome Atlas (TCGA) determined prevalence of ACSS subtypes and survival.⁷ Invasion assay was also performed on HCC cell.⁷ Inhibitors of fatty acid synthesis pathway were synthesized and tested in cancer cell lines, mouse models, and human clinical trials.^3,5 Results: Acetate alters HCC metabolism in hypoxia by histone acetylation of genes in acetate-mediated de novo fatty acid synthesis pathway resulting in increased expression of Fatty Acid Synthase, Acetyl-CoA Synthetase (ACSS), Acetyl-CoA Carboxylase-a as revealed by qPCR.² Acetate treated HCC display altered metabolism and increased oxygen consumption rate.⁴ Further, silencing ACSS genes leads to loss in histone acetylation indicating a central role for ACSS in lipogenesis.² Kaplan-Meier Analysis of TCGA indicates two ACSS2 subtypes, S1 and S2. ACSS2-S2 predominates in both cytoplasm and nucleus of HCC tumors and is associated with faster cancer progression.⁷ Nuclear ACSS is known to produce acetyl-CoA used in histone acetylation, further supporting ACSS important role in HCC metabolism. Although no therapies of this acetate-mediated pathway have been approved by FDA, ACSS2 inhibitors and FASN inhibitors display promising results in reducing tumor volume of breast cancer cells and mice models as well as increasing disease control rate in clinical trials, respectively.^3,5 Conclusion: Microbiota produced acetate, a short chain fatty acid modulates epigenetic mechanisms to upregulate HCC lipid synthesis. Inhibition of acetate-mediated metabolism reduces cancer cell viability and cancer progression suggesting that metabolic alteration caused by metabolite of gut microbes is important in pathogenesis of HCC and could provide clinically useful therapeutic targets.

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