LncRNAs-circRNAs as Rising Epigenetic Binary Superstars in Regulating Lipid Metabolic Reprogramming of Cancers

Abstract

As one of novel hallmarks of cancer, lipid metabolic reprogramming has recently been becoming fascinating and widely studied. Lipid metabolic reprogramming in cancer is shown to support carcinogenesis, progression, distal metastasis, and chemotherapy resistance by generating ATP, biosynthesizing macromolecules, and maintaining appropriate redox status. Notably, increasing evidence confirms that lipid metabolic reprogramming is under the control of dysregulated non-coding RNAs in cancer, especially lncRNAs and circRNAs. This review highlights the present research findings on the aberrantly expressed lncRNAs and circRNAs involved in the lipid metabolic reprogramming of cancer. Emphasis is placed on their regulatory targets in lipid metabolic reprogramming and associated mechanisms, including the clinical relevance in cancer through lipid metabolism modulation. Such insights will be pivotal in identifying new theranostic targets and treatment strategies for cancer patients afflicted with lipid metabolic reprogramming.

Keywords: cancer; cholesterol; circRNAs; fatty acids; lipid metabolic reprogramming; lncRNAs.

Figure 1

Rewiring of lipid metabolism in cancer. Lipid metabolism is a dynamic biological process that involves the endogenous de novo synthesis, exogenous import of fatty acids and cholesterol, fatty acid β oxidation, cholesterol efflux, biogenesis, and lipolysis of lipid droplets. Intracellular de novo lipogenesis begins with acetyl‐coenzyme A (acetyl‐CoA) derived from acetate by ATP‐citrate lyase (ACLY) or citrate by acetyl‐CoA synthetase (ACSS). Fatty acid synthesis requires acetyl‐CoA carboxylation into malonyl‐CoA by acetyl‐CoA carboxylases (ACC1/2), followed by the condensation of seven malonyl‐CoA molecules and one acetyl‐CoA molecule into the saturated 16‐carbon palmitate (16:0) by fatty acid synthase (FASN). Palmitate is then desaturated by stearoyl‐CoA desaturases (SCD) or elongated by fatty acid elongases (ELOVL) to form the monounsaturated 16‐carbon palmitoleate (16:1 n‐7) or 18‐carbon oleate (18:1 n‐9). Biogenesis of cholesterol also begins with acetyl‐CoA via the mevalonate pathway, which results in the synthesis of squalene and finally, cholesterol. Cancer cells can acquire fatty acids and cholesterol from various extracellular sources, such as LDL particles or fatty acid transport proteins. When lipids accumulate, cancer cells use these lipids to meet their energy consumption demand and redox homeostasis through fatty acid oxidation or β‐oxidation. Excess cholesterol is exported to the blood or converted into oxysterols through oxidation processes. Surplus fatty acids are esterified with glycerol or cholesterol into triglycerides and cholesteryl esters, which are incorporated into lipid droplets (LDs). When energy or membrane synthesis is needed, lipid droplets can be rapidly lipolyzed into free fatty acids and cholesterols to facilitate cancer cell proliferation and progression.

Figure 2

Transcriptional factors and oncogenic signaling pathways in lipid metabolism of cancer. Sterol regulatory element‐binding proteins (SREBPs) act as transcriptional factors that control the expression of most lipogenic enzymes involved in cholesterol and fatty acid biosynthesis. When lipid levels decrease, SREBPs are released from the SCAP‐INSIG complex in the endoplasmic reticulum and translocate to the Golgi, where they are cleaved by site‐1 and site‐2 proteases to release their active N terminus (mature SREBPs). Mature SREBPs move into the nucleus and bind to sterol response elements (SRE) in downstream target gene promoters to initiate transcription. The PI3K‐AKT‐mTOR pathway is frequently dysregulated in human cancers and can be activated by growth factor receptor tyrosine kinases (RTKs). The mTOR complexes participate in lipogenesis regulation through SREBP‐dependent or independent mechanisms. The mTOR‐dependent sequestration of Lipin‐1 in the cytoplasm enhances SREBP‐transcriptional activity in the nucleus, while the mTORC1/S6K1/SRPK2/U1‐70K axis increases mRNA splicing of lipogenic genes, such as FASN and ACLY. Liver X receptor (LXR) is an additional regulator of lipogenesis and a nuclear transcription factor receptor that senses oxysterols, cholesterol derivatives, to form the LXR‐RXRα complex. This complex induces the expression of genes involved in cholesterol efflux, such as ABCA1, and several lipogenic genes, including FASN and SCD. Peroxisome proliferator‐activated receptors (PPARs) are regulators of lipid metabolism and play vital roles in lipid β‐oxidation and storage in harsh environments when cellular energy is needed.

Figure 3

Potential mechanisms of lncRNAs & circRNAs in regulating gene expression. I) Regulation of genes transcription as a scaffold via binding with chromatin structure regulators; II) Regulation of gene transcription as a signal via recruiting transcriptional factors on promoter of target genes; III) Regulation of gene transcription as a guide via binding with histone modifying enzymes; IV) Decoying miRNAs as sponges; V) Modulating splicing of preliminary target mRNAs; VI) regulating target mRNA translation via binding with ribosome; VII) Functioning as templates to translate into micropeptides.

Figure 4

The lncRNAs & circRNAs in regulating lipogenesis of cancer. During the process of de novo lipogenesis, there are multiple rate‐limiting enzymes modulated by various lipid‐related lncRNAs and circRNAs to affect lipid metabolism reprogramming in cancer with distinct regulatory mechanisms. For de novo biogenesis of fatty acids, lncRNA TINCR and FLJ22763 have been identified to modulate ACLY expression in different cancer cells. The first rate‐limiting enzyme in the de novo synthesis of fatty acid, ACC1, has been shown to be regulated by circCAPRIN1, lncRNAs CTD‐2245E15.3 and TSPEAR‐AS2. With respect to other fatty acid synthetases, there are various lncRNAs and circRNAs involving the expression of these enzymes, functioning as the sponges of miRNAs, such as the lncRNA SNHG25/miR‐497‐5p/FASN axis, the circFARSA/miR‐330‐5p and miR‐326/FASN axis, the circ_0 008078/miR‐191‐5p/ELOVL4 axis, the circ_0 008078/miR‐191‐5p/ELOVL4 axis, the linc00174/miR‐145‐5p/SCD5 axis, and the circ_0000073/ miR‐1184/ FADS2 axis. For de novo biogenesis of cholesterols, lncRNAs ZFAS1 and AT102202 have been shown to regulate the expression of HMGCR, while lnc30 and circ_0000182 have been identified to modulate the expression of SQLE. Detailed mechanisms of these lipogenesis‐related lncRNAs and circRNAs in cancer are described in the main text.

Figure 5

The lncRNAs & circRNAs in regulating lipid transport, lipid droplets (LDs) metabolism, and lipolysis of cancer. With respect to lipid transport, lipid droplet metabolism, and lipolysis in cancer, various lipid‐related lncRNAs and circRNAs have been shown to play variable roles through the RNA‐RNA, RNA‐protein, and RNA‐DNA interactions. For the RNA‐RNA interaction, lipid‐related lncRNAs and circRNAs act as sponges of miRNAs to release miRNAs‐mediated repression of target genes, such as the circ_ABCB10/miR‐620/FABP5 axis in nasopharyngeal carcinoma (NPC), the circ_101 093/FABP3/ FABP3 axis in lung adenocarcinoma (LUAD), and the lncHCP5/miR‐3619‐5p/CPT1 axis in gastric cancer. For the RNA‐protein interaction, these lipid‐related lncRNAs and circRNAs hold the potential to bind transcriptional factors, posttranslational modifiers, or RNA‐ binding proteins to modulate the expression, stability and activation of key rate‐limiting enzymes. For instance, lncLNMICC binds transcriptional factor‐NPM1 to promote the expression of FABP5 in cervical cancer; lncRNA CCAT1 binds USP49 to regulate FKBP51‐mediated AKT phosphorylation, thereby promoting FABP5 expression in LUAD; lncRNA AGAP2‐AS1 binds HuR protein to enhance protein stability of CPT1 in MSC‐cocultured Breast cancer (BC). For the RNA‐DNA interaction, lncRNA BM450697 has been found to directly bind the DNA of the LDLR promoter, thereby inhibiting lipid uptake in hepatocellular carcinoma (HCC), while lncRNA HULC is able to induce methylation of CpG islands in the promoter of miR‐9 to promote ACSL1 expression and ACSL1‐mediated lipogenesis in HCC. Detailed mechanisms of these lncRNAs and circRNAs for lipid transport, LDs metabolism and lipolysis are described in the main text.

Figure 6

The lncRNAs & circRNAs in regulating lipid metabolic transcriptional factors and oncogenic signaling pathways of cancer. SREBP is the major transcriptional factor to regulate biogenesis of fatty acids and cholesterols at transcriptional levels. The lipid‐related lncRNAs and circRNAs in cancer can modulate the expression and stability of SREBPs through various regulatory mechanisms, including sponging miRNAs, binding protein and DNA, and affecting signaling pathways, even via modulating their regulators. Additionally, some lipid‐related lncRNAs and circRNAs have been shown to involve in regulating lipid metabolism in cancer via oncogenic signaling pathways, such as the PI3K‐AKT‐mTOR signaling pathway, the AKT/FoxO1/LXRα/RXR axis, and the p38 MAPK/PPARα signaling pathway. Detailed mechanisms of these lncRNAs and circRNAs in lipid metabolic transcriptional factors and oncogenic signaling pathways of cancer are described in the main text.