Metabolic reprogramming and epigenetic modifications in cancer: from the impacts and mechanisms to the treatment potential

Abstract

Metabolic reprogramming and epigenetic modifications are hallmarks of cancer cells. In cancer cells, metabolic pathway activity varies during tumorigenesis and cancer progression, indicating regulated metabolic plasticity. Metabolic changes are often closely related to epigenetic changes, such as alterations in the expression or activity of epigenetically modified enzymes, which may exert a direct or an indirect influence on cellular metabolism. Therefore, exploring the mechanisms underlying epigenetic modifications regulating the reprogramming of tumor cell metabolism is important for further understanding tumor pathogenesis. Here, we mainly focus on the latest studies on epigenetic modifications related to cancer cell metabolism regulations, including changes in glucose, lipid and amino acid metabolism in the cancer context, and then emphasize the mechanisms related to tumor cell epigenetic modifications. Specifically, we discuss the role played by DNA methylation, chromatin remodeling, noncoding RNAs and histone lactylation in tumor growth and progression. Finally, we summarize the prospects of potential cancer therapeutic strategies based on metabolic reprogramming and epigenetic changes in tumor cells.

Fig. 1. Metabolic reprogramming pathways and epigenetic modification marks interact in cancer.

In cancer cells, metabolic pathways are altered during tumorigenesis and development, exhibiting regulated metabolic plasticity. Cancer metabolic reprogramming involves mainly a shift from oxidative phosphorylation to aerobic glycolysis, increased pentose phosphate pathway and serine synthesis pathway activation, and enhanced lipid and amino acid metabolism in cancer cells, providing essential raw materials and energy support for tumor growth, participating in the tumor immune response, and maintaining redox homeostasis in the tumor microenvironment. Metabolic changes are often closely related to epigenetic changes. The mechanisms of epigenetic modification mainly include DNA methylation, histone modification, chromatin remodeling and noncoding RNA functions. Epigenetic modification marks and metabolic reprogramming pathways interact to play an essential role in tumorigenesis and development.

Fig. 2. DNA methylation affects tumor initiation and progression.

a In pre-adenocarcinoma in the lung, DNA hypermethylation caused by functional mutation of TET downregulates the expression of Wnt antagonist genes, triggering abnormal activation of Wnt signaling and accelerating the formation of early tumor lesions. b DNMT1-mediated hypermethylation of the estrogen receptor (ER) promoter region inhibits the expression of the ER gene during the epithelial-mesenchymal transition, promoting the EMT, which required for metastasis, thereby promoting the proliferation of cancer stem cells in triple-negative breast cancer (TNBC). c Zinc finger ZNF377 negatively regulates the glucose metabolism pathway in tumor cells to exert a significant antitumor effect. d SLC27A6 increases the tumor cell metastatic potential by promoting lipid biosynthesis. DNA hypermethylation downregulates the expression of SLC27A6, which promotes the proliferation of nasopharyngeal carcinoma via the regulation of lipid metabolism.

Fig. 3. Lactate metabolism and histone lysine lactylation in cancer cells.

a Lactic acid in the body is derived mainly from the metabolites of glycolysis. Histone lactylation refers mainly to the posttranslational modification of histone lysine residues with lactate as the substrate. Hypoxia and M1 macrophages promote histone lactylation. b Histone lactylation promotes the expression of YTHDF2, which promotes the degradation of the mRNA of tumor suppressor genes Per1 and TP53, accelerating ocular melanoma tumorigenesis. c The M6A modification of JAK1 mRNA in TIM cells is mediated by the lactylation of METTL3 at K281 and K345 and promotes the immunosuppression of tumor-infiltrating myeloid cells. d In non-small cell lung cancer, histone lactylation regulates the expression levels of metabolic enzymes that modulate cancer cell glycolysis. e Lactic acid-producing bacteria may promote gastric carcinogenesis by increasing lactate levels and lactylation rates. f In pancreatic ductal adenocarcinoma, increased tumor cell-produced lactate flux mediates epigenetic reprogramming to regulate the formation of human pancreatic CAFs.

Fig. 4. Histone modifications in cancer.

Histone tails can be posttranslationally modified by various molecules in the presence of enzymes. Examples include histone methylation, acetylation, phosphorylation, glycosylation, guanylation, succinate, SUMO, and ubiquitination. These histone posttranslational modifications are involved in protein expression and degradation, changes in enzymatic activity, signaling, energy production, the immune response, and various other cancer cell activities.