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Review

Metabolism-Associated Epigenetic and Immunoepigenetic Reprogramming in Liver Cancer

Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
*
Authors to whom correspondence should be addressed.
These authors contributed equally to the manuscript.
Academic Editor: Vangelis Kondylis
Cancers 2021, 13(20), 5250; https://doi.org/10.3390/cancers13205250
Received: 14 September 2021 / Revised: 13 October 2021 / Accepted: 16 October 2021 / Published: 19 October 2021
(This article belongs to the Special Issue Cell Death, Inflammation, and Liver Cancer)
Liver cancer is one of the most frequently occurring cancer types and one of the leading causes of cancer-related mortality globally. Despite of its constantly growing incidence, the efficacy of the current therapeutic interventions is limited. Metabolic and epigenetic aberrations are two distinct but mutually influential factors which contribute to the plasticity and adaptability of tumor cells to a hostile microenvironment, leading to high resilience and permissive conditions. This review offers the most up-to-date overview of the recently reported major metabolic dysregulations in liver cancer cells, the consequential epigenetic reprogramming, as well as the opportunity to explore the effect on metabolic competition and inhibition of immune cells in the tumor microenvironment. Finally, we discuss the potential therapeutic value of pharmaceutical inhibition of these essential pathways in combating liver cancer.
Metabolic reprogramming and epigenetic changes have been characterized as hallmarks of liver cancer. Independently of etiology, oncogenic pathways as well as the availability of different energetic substrates critically influence cellular metabolism, and the resulting perturbations often cause aberrant epigenetic alterations, not only in cancer cells but also in the hepatic tumor microenvironment. Metabolic intermediates serve as crucial substrates for various epigenetic modulations, from post-translational modification of histones to DNA methylation. In turn, epigenetic changes can alter the expression of metabolic genes supporting on the one hand, the increased energetic demand of cancer cells and, on the other hand, influence the activity of tumor-associated immune cell populations. In this review, we will illustrate the most recent findings about metabolic reprogramming in liver cancer. We will focus on the metabolic changes characterizing the tumor microenvironment and on how these alterations impact on epigenetic mechanisms involved in the malignant progression. Furthermore, we will report our current knowledge about the influence of cancer-specific metabolites on epigenetic reprogramming of immune cells and we will highlight how this favors a tumor-permissive immune environment. Finally, we will review the current strategies to target metabolic and epigenetic pathways and their therapeutic potential in liver cancer, alone or in combinatorial approaches. View Full-Text
Keywords: liver cancer; immunometabolism; Warburg effect; acetyl-CoA; SAM; resminostat; metformin; guadecitabine; combinatorial therapy liver cancer; immunometabolism; Warburg effect; acetyl-CoA; SAM; resminostat; metformin; guadecitabine; combinatorial therapy
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MDPI and ACS Style

Fan, C.; Kam, S.; Ramadori, P. Metabolism-Associated Epigenetic and Immunoepigenetic Reprogramming in Liver Cancer. Cancers 2021, 13, 5250. https://doi.org/10.3390/cancers13205250

AMA Style

Fan C, Kam S, Ramadori P. Metabolism-Associated Epigenetic and Immunoepigenetic Reprogramming in Liver Cancer. Cancers. 2021; 13(20):5250. https://doi.org/10.3390/cancers13205250

Chicago/Turabian Style

Fan, Chaofan, Shing Kam, and Pierluigi Ramadori. 2021. "Metabolism-Associated Epigenetic and Immunoepigenetic Reprogramming in Liver Cancer" Cancers 13, no. 20: 5250. https://doi.org/10.3390/cancers13205250

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