LncRNA-mediated posttranslational modifications and reprogramming of energy metabolism in cancer

Abstract

Altered metabolism is a hallmark of cancer, and the reprogramming of energy metabolism has historically been considered a general phenomenon of tumors. It is well recognized that long noncoding RNAs (lncRNAs) regulate energy metabolism in cancer. However, lncRNA-mediated posttranslational modifications and metabolic reprogramming are unclear at present. In this review, we summarized the current understanding of the interactions between the alterations in cancer-associated energy metabolism and the lncRNA-mediated posttranslational modifications of metabolic enzymes, transcription factors, and other proteins involved in metabolic pathways. In addition, we discuss the mechanisms through which these interactions contribute to tumor initiation and progression, and the key roles and clinical significance of functional lncRNAs. We believe that an in-depth understanding of lncRNA-mediated cancer metabolic reprogramming can help to identify cellular vulnerabilities that can be exploited for cancer diagnosis and therapy.

Keywords: cancer metabolism; enzyme; long noncoding RNA; metabolic reprogramming; posttranslational modification.

FIGURE 1

LncRNA‐mediated posttranslational modification of metabolic enzymes. LncRNA‐mediated posttranslational modifications directly affect metabolic enzymes to reprogram glucose metabolism. Examples are phosphorylation and ubiquitination of PFKFB3 by AGPG and YIYA; ubiquitination of PGK1 by MetaLnc9 and GBCDRlnc1; ubiquitination of PKM2 by AC020978, FEZF1‐AS1, and LINC01554; and phosphorylation of PKM2 and LDHA by HULC. LncRNA: long noncoding RNA; PFKFB3: 6‐phosphofructo‐2‐kinase/fructose‐2,6‐bisphosphatase 3; AGPG: actin gamma 1 pseudogene; PGK1: phosphoglycerate kinase 1; PKM2: pyruvate kinase muscle isozyme M2; FEZF1‐AS1: Fez family zinc finger protein 1 antisense ribonucleic acid 1; LDHA: lactate dehydrogenase A; HULC: highly up‐regulated in liver cancer; P, phosphorylation; Ub, ubiquitination; GLUT: glucose transporter isoform; HK2: hexokinase 2; F6P: fructose 6‐phosphate; F‐1,6‐BP: fructose‐1,6‐bisphosphate;F‐2,6‐BP: fructose‐2,6‐bisphosphate; 1,3‐BPG: 1,3‐bisphosphoglycerate; 3‐PG: 3‐phosphoglycerate; 2‐PG: 2‐phosphoglycerate; ENO: enolase; PEP: phosphoenolpyruvate

FIGURE 2

LncRNA‐mediated posttranslational modification of transcription factors. LncRNA‐mediated posttranslational modification of transcription factors regulates aerobic glycolysis‐related genes. Examples are hydroxylation, phosphorylation, and ubiquitination of HIF‐1α by HISLA, LINK‐A, lincRNA‐p21, and MALAT1, respectively; ubiquitination of c‐Myc by MEG3, GLCC1, and XLOC_006390; and phosphorylation and ubiquitination of NF‐κB by CamK‐A, KRT19P3, and DRAIC. LncRNA: long noncoding RNA; HIF‐1α: hypoxia‐inducible factor‐1α; HISLA: HIF‐1α‐stabilizing lncRNA; LINK‐A: long intergenic noncoding RNA for kinase activation; lincRNA: long intergenic noncoding RNA; MALAT1: metastasis‐associated lung adenocarcinoma transcript 1; MEG3: maternally expressed gene 3; GLCC1: glycolysis‐associated lncRNA of colorectal cancer 1; NF‐κB: nuclear factor κB; CamK‐A: lncRNA for calcium‐dependent kinase activation; KRT19P3: keratin 19 pseudogene 3; DRAIC: downregulated RNA in cancer; H: hydroxylation; P, phosphorylation; Ub, ubiquitination; GLUT: glucose transporter isoform; HK2: hexokinase 2; ENO1: enolase 1; LDHA: lactate dehydrogenase A; PKM2: pyruvate kinase muscle isozyme M2

FIGURE 3

LncRNA‐mediated posttranslational modification of other proteins involved in metabolic pathways. LncRNA‐mediated posttranslational modifications of metabolic pathways include phosphorylation of AMPK signalling pathway components by MACC1‐AS1, NBR2, LINP1, and ANRIL; phosphorylation of PI3K/AKT signalling pathway components by LINC00184, AK023948, LINC00470, and LOC572558; and phosphorylation, ubiquitination, and acetylation of p53 signalling pathway components by LOC572558, LINK‐A, PRAL, and MALAT1. LncRNA: long noncoding RNA; AMPK: adenosine monophosphate‐activated protein kinase; MACC1: metastasis‐associated in colon cancer‐1; NBR2: neighbour of BRCA1 gene 2; LINP1: lncRNA in nonhomologous end joining pathway 1; ANRIL: antisense noncoding RNA in the INK4 locus; PI3K: phosphoinositide‐3‐kinase; LINK‐A: long intergenic noncoding RNA for kinase activation; PRAL: p53 regulation‐associated lncRNA; MALAT1: metastasis‐associated lung adenocarcinoma transcript 1; Ac, acetylation; P, phosphorylation; Ub, ubiquitination; HNF4α: hepatocyte nuclear factor 4 alpha; DHX9: DEAH (Asp‐Glu‐Ala‐ His) box helicase proteins 9; FUS: fused in sarcoma; MDM2: murine double minute 2; HSP90: heat shock protein 90; SIRT1: Sirtuin 1