The impact of RNA binding proteins and the associated long non-coding RNAs in the TCA cycle on cancer pathogenesis

Abstract

The tricarboxylic acid (TCA) cycle is a central route for generating cellular energy and precursors for biosynthetic pathways. Emerging evidences have shown that the aberrations of metabolic enzymes which affect the integrity of TCA cycle are implicated in various tumour pathological processes. Interestingly, several TCA enzymes exhibit the characteristics of RNA binding properties, and their long non-coding RNA (lncRNA) partners play critical regulatory roles in regulating the function of TCA cycle and tumour progression. In this review, we will discuss the functional roles of RNA binding proteins and their lncRNA partners in TCA cycle, with emphasis placed on the cancer progression. A further understanding of RNA binding proteins and their lncRNA partners in TCA cycle, as well as their molecular mechanisms in oncogenesis, will aid in developing novel layers of metabolic targets for cancer therapy in the near future.Abbreviations: CS: citrate synthase. AH: aconitase, including ACO1, and ACO2. IDH: isocitrate dehydrogenase, including IDH1, IDH2, and IDH3. KGDHC: α-ketoglutarate dehydrogenase complex, including OGDH, DLD, and DLST. SCS: succinyl-CoA synthase, including SUCLG1, SUCLG2, and SUCLA2. SDH: succinate dehydrogenase, including SDHA, SDHB, SDHC, and SDHD. FH: fumarate hydratase. MDH: malate dehydrogenase, including MDH1 and MDH2. PC: pyruvate carboxylase. ACLY: ATP Citrate Lyase. NIT: nitrilase. GAD: glutamate decarboxylase. ABAT: 4-aminobutyrate aminotransferase. ALDH5A1: aldehyde dehydrogenase 5 family member A1. ASS: argininosuccinate synthase. ASL: adenylosuccinate synthase. DDO: D-aspartate oxidase. GOT: glutamic-oxaloacetic transaminase. GLUD: glutamate dehydrogenase. HK: hexokinase. PK: pyruvate kinase. LDH: lactate dehydrogenase. PDK: pyruvate dehydrogenase kinase. PDH: pyruvate dehydrogenase complex. PHD: prolyl hydroxylase domain protein.

Keywords: RNA binding protein; TCA cycle; TCA cycle enzymes; long non-coding RNA; tumour progression.

Figure 1.

Biochemical reactions that drive the TCA cycle. By integrating the KEGG metabolic pathways (https://www.genome.jp/kegg/pathway.html#metabolism, hsa00010, hsa00020, hsa00071, and hsa00250), the biochemical reactions in TCA cycle were summarized. The TCA cycle is comprised of 8 steps, three of which are irreversible, including CS-driven the generation of citrate from oxaloacetate and acetyl-CoA; IDH-driven the conversion of isocitrate to α-KG; and KGDHC-driven the formation of succinyl-CoA from α-KG (hsa00020). Acetyl-CoA derived from pyruvate, which is the end product of glycolysis, is the typical input for the TCA cycle (hsa00010). In addition, outside sources, including the production of acetyl-CoA from β-oxidation of fatty acids (hsa00071), the production of fumarate, succinate, and α-ketoglutarate from protein catabolism (hsa00250), and the production of oxaloacetate from pyruvate (hsa00010), can also provide the intermediates in the TCA cycle.

Figure 2.

Interplay among TCA cycle, glycolysis, and tumorigenic signalling. Oncogenic mutations of IDH lead to the production of 2-HG. Deficiencies of SDH and FH in cancer cells elevate succinate and fumarate, respectively. Accumulation of 2-HG, succinate, and fumarate inhibits the degradation of HIF-1α, and results in HIF-1α’s nuclear translocation, which brings about the interaction of HIF-1α and the hypoxia response element (HRE) and thus promotes a plethora of tumour-related genes. The downstream genes of HIF-1α include glycolytic enzymes (e.g. HK, PK, LDH) and PDK, which promote the catabolism of glucose through aerobic glycolysis and shift glucose away from the TCA cycle. In addition, the accumulation of fumarate also stabilizes NRF2 through either altering cellular redox state via succination of GSH or a direct succination of its negative regulator KEAP1. Also, NRF2 can translocate to the nucleus and function as a transcriptional factor through interacting with the antioxidant response element (ARE) upon the promoter of multiple tumour-related genes.

Figure 3.

Mechanisms of lncRNAs in regulating TCA cycle enzymes. TINCR binds to ACLY and protects it from ubiquitin degradation to maintain total cellular acetyl-CoA levels. LINC00477 interacts with ACO1 and suppresses the conversion ability from citrate to isocitrate by ACO1. IDH1-AS1 enhances IDH1 enzymatic activity through promoting its homodimerization, leading to increased production of α-KG. GAS5 inhibits FH – MDH2–CS complex formation by increasing SIRT3-mediated MDH2 deacetylation. AC020978 binds to MDH2 and protects it from ubiquitin degradation.