Metabolism-Associated Epigenetic and Immunoepigenetic Re-programming in Liver Cancer

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1		Chaofan Fan	+ 2110 word(s)	2110	2021-11-03 06:59:42

This entry is adapted from the peer-reviewed paper 10.3390/cancers13205250

Metabolic reprogramming and epigenetic changes have been characterized as hallmarks of liver cancer. 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. 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.

liver cancer immunometabolism epigenetics tumor micro-environment metabolic treatment immunotherapy epigenetic treatment

1. Introduction

Liver cancer is the fourth most common cause of cancer death worldwide ^[1]. No effective liver cancer therapy has been approved so far and therefore there is an urgent need to find efficient and safe therapeutic strategies. Liver cancer is induced by several pathological processes normally related to chronic inflammation, such as metabolic and nutritional disturbances (ASH/NASH) as well as viral infections (HBV/HCV) ^[2]. Generally, conditions leading to hepatocyte stress or damage inevitably result in alterations of their metabolic activity. Vice-versa, loss of the energetic balance could impair the functionality of cellular organelles leading to hepatocyte damage. Accordingly, the oncogenic transformation of hepatocytes towards a malignant phenotype is characterized by dramatic changes of the cellular metabolism referred to as metabolic reprogramming. It is nowadays clear from experimental models and clinical evidence that many oncogenic mutations selectively induce metabolic changes that critically sustain tumor growth. However, in liver cancer, not only the genomic landscape but also the immune characteristics of transforming cells frequently define the microenvironment that dictates a distinct metabolic profile of the tumor, as, for instance, in the case of NASH-related HCC ^[3]. In turn, metabolites produced by cancer cells generate a permissive immune-microenvironment for favorable growing conditions. Alterations of the cellular metabolism occurring in transforming malignant cells markedly influence the epigenetic mechanisms and, in return, epigenetic modifications commonly sustain the metabolic reprogramming through the regulation of specific genes ^[4].

In this review, we describe the most important changes of the metabolism characterizing and supporting hepatocarcinogenesis. We will illustrate how these changes of cellular metabolism impact on epigenetic modifications highlighting the most recent findings about the major alterations of the chromatin occurring in liver cancer cells. Successively, we will describe how metabolic reprogramming of liver cancer can possibly influence the tumor immune-microenvironment and how epigenetic alterations of the immune cells can affect cancer growth. Finally, we will review the most novel findings about current therapeutic strategies aiming to modulate cancer-specific metabolic pathways and epigenetic modifications in order to render cancer more vulnerable to conventional therapies.

Figure 1. Metabolic reprogramming of liver cancer cells and exhausted immune effector cells in the tumor microenvironment.

2. Metabolic Reprogramming in Liver Cancer

2.1. Glycolysis

Anaerobic glycolysis is the first form of metabolic reprogramming described in liver cancer. Hypoxia is a central determinant of changes affecting glucose metabolism, triggering a switch from oxidative to glycolytic metabolism ^[5]. In fact, the expression of the most important rate limiting enzymes involved in glycolysis is frequently altered in liver cancer ^[6]. Of note, HIF1α also regulates the expression of the glucose transporter GLUT1 which resulted to be upregulated in HCC and to be associated with tumor histological grade ^[7].

2.2. TCA Cycle and Lipid Metabolism

The tricarboxylic acid cycle (TCA) is a central metabolic pathway regulating cellular energy production as well as to the maintenance of the cellular redox balance. The TCA cycle activity and the expression of several rate-limiting enzymes were shown to be altered in the liver of patients with HCC ^[8]. α-ketoglutarate (α-KG) also originates in the TCA cycle from isocitrate. This reaction is catalyzed by the cytoplasmic enzyme isocitrate dehydrogenase 1 (IDH1) with reduction of NADP into NADPH. Gain of function mutations of the isoforms IDH1 and IDH2 are frequently observed in human CCA ^[9].

Abnormalities of lipid metabolism have been abundantly reported in the context of liver cancer. In particular, de novo lipogenesis was shown to be preferentially used as a source of fatty acids by hepatic cancer cells ^[10]. However, the beneficial effects of lipogenic inhibition on cancer growth seem to be dependent on the oncogenes driving the process as well as on the microenvironmental profile ^[11]. CTNNB1-mutated HCC seems to promote FAO rather than glycolysis and this phenotype is dependent on PPAR-α expression as shown in transgenic mouse models and CTNNB1-mutated human HCCs ^[12].

2.3. Amino Acids Metabolism

Beyond lipid and glucose metabolism, another relevant source of carbon in highly proliferating cells derives from the amino acids metabolism ^[13]. Glutamine is the most abundant amino acid consumed by liver cancer cells at high rates ^[14]. Glutamine synthetase (GS) is the enzyme responsible for glutamate conversion to glutamine and it is frequently overexpressed in liver cancer associated with CTNNB1 mutations ^[15]. It was shown that myc-driven liver tumors are particularly sensitive to oxidative stress because of their reduced glutathione production ^[16]. Human HCC and liver tumors from transgenic c-Myc were shown to display a defective methionine metabolism with increased level of the enzyme S-adenosylmethionine synthase isoform type-1 (MAT-1) ^[17].

2.4. One-Carbon Metabolism

In relation to cancer-related alterations of amino acid metabolism, one-carbon metabolism also represents an important pathway for nucleotide synthesis and reducing agents generation as well as a substrate donor for methylation reactions. The enzyme methylenetetrahydrofolate dehydrogenase 1–like (MTHFD1L), critically involved in the folate cycle and responsible for the redox transformation of THF, was recently shown to play an essential role in hepatoma cell lines growth and proliferation as well as to be overexpressed in the liver of HCC patients ^[18].

3. Metabolic Reprogramming Leading to Epigenetic Changes in Tumor Cells

Metabolic reprogramming accompanying hepatic carcinogenesis not only affects cell functionality and activity by changing the energetic balance and the availability of substrates, but it also influences the expression of genes regulating cell metabolism. This transcriptional tuning occurs mainly through the accumulation of metabolites that boost the enzymatic activity of epigenetic regulators. The most common metabolites that function as substrate for chromatin modifications are SAM, acetyl-CoA and nicotinamide adenine dinucleotide (NAD⁺) as well as α-KG, and are tightly dependent on alterations of the metabolic pathways previously described. They are responsible for most of the acetylation and methylation processes of DNA and histones and they are commonly altered in the context of hepatocarcinogenesis (Figure 2).

Figure 2. Metabolism-related epigenetic modifications in liver cancer cells and immune cells.

3.1. DNA Methylation

As in many other cancer types, abnormal hypermethylation and hypomethylation of chromatin components, DNA and histones, are frequent alterations occurring in liver cancer ^[19]. Gene expression of the isoforms DNMT1, DNMT3a, and DNMT3b was shown to be upregulated in correlation with the number of methylated genes in HCCs as compared to normal liver ^[20].

3.2. Histone Modifications

The reactions of acetylation that interest mainly histones are catalyzed by histoneacetyltransferases (HATs) that use as a substrate Acetyl-Co-A to acetylate lysine residues present on the protein. A very recent proteomic study showed that HAT1 is significantly elevated in human HCC and CCA ^[21]. On the contrary, histone deacetylases (HDACs) remove the acetyl groups on the lysine residues. The isoform HDAC8 was shown to drive NASH-induced HCC through a de-repression of the β-catenin pathway ^[22] (Figure 2).

3.3. ATP-Dependent Chromatin Remodeling

A further level of epigenetic regulation is also exerted by ATP-dependent remodeling complexes that enable dynamic restructuring of chromatin density in the nucleosome with energy derived from ATP hydrolysis. ARID2 is one of those complexes that was shown to be negatively correlated with HCC metastasis and positively with patient survival ^[23].

4. Metabolism of the Immune Cells in the Microenvironment of Liver Cancer

The discussed tumor metabolic reprogramming gives rise to a suboptimal metabolic microenvironment for infiltrated immune cells. These conditions have a pivotal role in driving the exhaustion of immune effector cells, in particular CD8⁺ T cell and NK cell exhaustion, which in turn provokes immune evasion (Figure 1).

4.1. Glycolysis

T cell receptor (TCR) dependent CD8⁺ T cells activation involves an initial switch from oxidative phosphorylation to glycolysis ^[24]. This short-term metabolic reprogramming boosts the early translation of IFN-γ, TNF-α, and IL-2 transcripts. Thereafter, long-term glycolytic reprogramming is induced by co-stimulatory signaling of CD28, via the Akt/mTOR and HIF-1α pathway to promote Glut1-dependent glucose uptake as well as the expression of glycolytic enzymes, which sustains the increasing energetic and biosynthetic demands. Due to the biological importance of the glycolytic pathway, scarcity of glucose in the TME imposes a major hurdle for effector T cell activity. Sole restriction of glucose availability limits CD8⁺ T cell responsiveness, despite the presence of tumor antigenic stimulation ^[25].

4.2. TCA Cycle, Glutaminolysis, and Fatty Acid Oxidation

As discussed, deprivation of glucose in the TME and immune checkpoint signaling can both suppress glycolysis, forcing immune cells to switch to fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS). The overexpression of the FAO rate-limiting enzyme CPT1A by PD-1 signaling has been shown to be responsible for such a shift in energy production. Loss of mitochondrial function results in the subsequent elevation of intra-cellular ROS level, which prevents the dephosphorylation of NFAT, causing the persistent signaling that eventually drives T cell exhaustion ^[26]. Conversely, regulatory T cells (Treg) appear to be able to thrive in the TME, despite of the adverse nutritional context.

Glutamine is one of the major carbon sources in cells, and it fuels the TCA cycle in the form of α-KG generated from glutaminolysis. Abolishment of this catabolic process skews macrophage polarization towards the M1 phenotype, and leads to the reduction of myeloid-derived suppressor cells (MDSCs), rendering the tumor more susceptible to immune checkpoint therapy ^[27].

4.3. One-Carbon Metabolism

Methionine influx and metabolism are crucial for T cell activation upon stimulation of antigen receptors, nucleic acids, and reducing agents, together with crucial precursors and co-factors to maintain critical biological processes ^[28]. GSH is required to mitigate the ROS triggered by TCR-mediated T cell activation. This antioxidant mechanism upregulates MYC production via the NFAT-mTOR axis to initiate reprogramming of glucose metabolism and facilitate T cell proliferation and cytokine secretion ^[29].

5. Metabolism-Regulated Immunoepigenetic Changes in Liver Cancer

Similar to the case of cancer cells, the aforementioned metabolic aberrations also contribute to the epigenetic reprogramming of immune cells. Here, we highlight the epigenetic changes of immune cells under the context of tumor-induced metabolic reprogramming.

5.1. Glycolysis and TCA Cycle-Associated Epigenetic Modifications

Acetyl-CoA is a metabolic intermediate connecting glycolysis to the TCA cycle. TLR activation in macrophages induces upregulation of glycolysis and ATP citrate lyase activity to yield acetyl-CoA, which facilitates the histone H3 and H4 acetylation of specific innate immune responsive gene sets to increase enhancer accessibility ^[30]. A similar mechanism was also observed in CD4⁺ T cells, where activated T cells upregulate LDHA expression to maximize aerobic glycolysis. This results in histone H3 acetylation of both the promoter and enhancer of IFN-γ, and ultimately promotes effector T cell differentiation [106]. Under glucose deprivation, CD8⁺ T cells were shown to uptake extracellular acetate through MCT-1 and MCT4, and then converted it into acetyl-CoA by ACSS2 for histone H3 and H4 acetylation of cytokine genes to maintain effector function in adverse conditions ^[31].

5.2. One-Carbon Metabolism-Associated Epigenetic Modifications

The metabolite intermediate of the methionine cycle, SAM, plays a major role as the universal methyl donor in DNA and histone methylation. For instance, in HCC, high concentration of SAM and MTA leads to lowered accessibility of key T cell activation gene sets which are involved in lymphocyte proliferation and differentiation, and hence skewing towards an exhaustion phenotype ^[32].

6. Metabolic Targets in the Treatment of Liver Cancer

In the last decade, many studies have been focused on the development of metabolic inhibitors as supplemental approach for cancer therapy. Here, we discuss the recent advancement of metabolic strategies for liver cancer and anti-tumor immunity (Table 2).

7. Epigenetic Targets in the Treatment of Liver Cancer

In the liver, mutations and altered expression of epigenetic modifiers in relation to driven metabolic rewiring are common, and tackling these epigenetic changes can be exploited to increase the efficacy of therapies against liver cancer ^[33]. Current epigenetic-regulating strategies for liver cancer therapy are reviewed here (Table 3).

8. Conclusions and Outlook

To date, liver cancer remains as one of the deadliest cancer types, and its global incidence rate continues to grow steadily. The current therapeutic options for advanced liver cancer are limited and often shows unsatisfactory benefits in patients. With the development and testing of novel metabolic and epigenetic inhibitors, it opens up new opportunities to interfere with cancer metabolism, epigenetic dysregulation, and normalize the immune microenvironment to enhance potentially anti-cancer immunity.

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