m6A-regulated tumor glycolysis: new advances in epigenetics and metabolism

Abstract

Glycolytic reprogramming is one of the most important features of cancer and plays an integral role in the progression of cancer. In cancer cells, changes in glucose metabolism meet the needs of self-proliferation, angiogenesis and lymphangiogenesis, metastasis, and also affect the immune escape, prognosis evaluation and therapeutic effect of cancer. The n6-methyladenosine (m6A) modification of RNA is widespread in eukaryotic cells. Dynamic and reversible m6A modifications are widely involved in the regulation of cancer stem cell renewal and differentiation, tumor therapy resistance, tumor microenvironment, tumor immune escape, and tumor metabolism. Lately, more and more evidences show that m6A modification can affect the glycolysis process of tumors in a variety of ways to regulate the biological behavior of tumors. In this review, we discussed the role of glycolysis in tumor genesis and development, and elaborated in detail the profound impact of m6A modification on different tumor by regulating glycolysis. We believe that m6A modified glycolysis has great significance and potential for tumor treatment.

Keywords: Glycolysis; Tumor; Tumor therapy; m6A.

Fig. 1

Regulation of m6A modification. The writers and erasers of m6A are responsible for regulating the methylation level of related RNA. Then, various m6A readers can recognize and combine with m6A modified RNA to regulate gene expression. METTL3, Methyltransferase-like 3; METTL14, Methyltransferase-like 14; WTAP, Wilms tumor 1-associated protein; RBM15, RNA binding motif protein 15; VIRMA, Vir-like m6A methyltransferase associated; ZC3H13, zinc finger CCCH-type containing 13; METTL16, Methyltransferase-like 16; METTL5, Methyltransferase-like 5; ZCCHC4, zinc finger CCHC-type containing 4; FTO, Fat mass and obesity-associated protein; ALKBH3, ALKB homologue 3; ALKBH5, ALKB homologue 5; YTHDF1, YTH N6-Methyladenosine RNA Binding Protein 1; YTHDF2, YTH N6-Methyladenosine RNA Binding Protein 2; YTHDF3, YTH N6-Methyladenosine RNA Binding Protein 3; YTHDC1, YTH Domain Containing 1; YTHDC2, YTH Domain Containing 2; HNRNPA2B1, Heterogeneous nuclear ribonucleoprotein A2B1; HNRNPAC/G, Heterogeneous nuclear ribonucleoprotein C/G; HNRNPR, Heterogeneous nuclear ribonucleoprotein R; IGF2BP1-3, Insulin Like Growth Factor Binding Protein 1–3; NKAP, NF-κB activating protein; eIF3, Eukaryotic translation initiation factor 3

Fig. 2

The relationship between glycolysis and tumors. In the upper part of the figure, the glycolysis pathway is depicted for both normal and tumor cells, with a focus on the involvement of m6A regulators in glucose metabolism. The lower part of the figure illustrates how glycolysis impacts various aspects of tumor biology, including proliferation, angiogenesis and lymphangiogenesis, metastasis, immune escape, and its relevance to tumor prognosis evaluation and treatment. (I) Changes in glycolysis enzymes within tumor cells influence tumor proliferation by affecting glycolysis. (II) Enhanced tumor glycolysis contributes to angiogenesis and lymphangiogenesis. (III) Elevated tumor glycolysis promotes tumor metastasis. (IV) Increased tumor glycolysis inhibits the activity of T and NK cells, affects PD-L1 expression, and promotes the generation of MDSCs, thereby inducing tumor immune escape. (V) The substantial uptake of 18 F-FDG by tumor cells leads to the accumulation of FDG-6-phosphate, which can be imaged using PET/CT. (VI) Attenuation of tumor glycolysis inhibits proliferation, enhances chemosensitivity, and promotes apoptosis in cancer cells

Fig. 3

m6A regulates tumor glycolysis. Writers, erasers and readers of m6A participate in tumor glycolysis by regulating glycolysis related enzymes or pathways in a series of direct or indirect ways, and ultimately affect the genesis and development of tumors

Fig. 4

Clinical significance of m6A-regulated tumors glycolysis. m6A regulation impacts the efficacy of tumor chemotherapy, immunotherapy, and targeted therapy by influencing glycolysis. Additionally, m6A inhibitors exert anti-tumor effects by inhibiting glycolysis