Malignant cells are known for accelerated nutrient and energy metabolism and increased glucose metabolism and uptake. In eukaryotic cells, glucose transport consists of two different types of membrane-related carrier proteins, namely, Na
+-glucose linked transporters (SGLTs) and glucose transporters (GLUTs) [
35]. GLUTs play a crucial role in glucose metabolism in transformed cells [
36,
37]. A number of lncRNAs can regulate glycolytic steps by binding GLUTs. A novel large antisense non-coding RNA (named ANRIL) spans a 126.3 kb region and transcribes as a 3.8 kb lncRNA in the antisense orientation of the INK4B-ARF-INK4A gene cluster [
16,
38,
39]. ANRIL is upregulated in nasopharyngeal carcinoma (NPC). By activating the AKT/mTOR signal, ANRIL upregulates GLUT1 and LDHA expression, thus increasing glucose uptake and promoting cancer progression in NPC cells [
40]. Adenosine monophosphate-activated protein kinase (AMPK) is a critical sensor of cellular energy status in eukaryotic cells, and activated AMPK functions to promote catabolic processes (such as glycolysis, FA oxidation, and autophagy) and repress anabolic processes (such as lipid, protein, and sterol synthesis), resulting in restoration of the energy balance [
41]. As anabolic processes are often required to support tumor survival and growth, the AMPK signaling pathway plays tumor-suppressive roles in many types of cancers. Currently, a glucose starvation-induced lncRNA called NBR2 (the neighbor of BRCA1 gene 2) was found to be induced in cancer cells by the LKB1–AMPK pathway under energy stress conditions [
42]. Intriguingly, NBR2 can in turn interact with the kinase domain of AMPKα and promote AMPK kinase activity, thus forming a feed-forward loop to potentiate AMPK activation upon glucose starvation [
34]. However, under the energy stress imposed by phenformin treatment, NBR2 promotes glucose uptake by upregulating GLUT1 expression but not by affecting phenformin-induced AMPK activation [
43]. Thus, NBR2 may promote cancer cell glucose uptake by participating in alterable biological processes in response to different intracellular environments. GLUT4 is directly associated with carbohydrate metabolism. It translocates to the plasma membrane and facilitates the intracellular transport of glucose under insulin stimulation [
44]. Ellis et al. found that the lncRNA CRNDE, which is upregulated in colorectal tumors, whereas little to none is expressed in the normal colorectal epithelium [
45], can positively regulate GLUT4 transcription and glucose intake [
30].
In addition to binding to glycolysis transporters, lncRNAs can also regulate glycolytic steps by binding to key enzymes (Fig.
2). The glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2 (PFKFB2) acts as a functional homodimer that catalyzes both the synthesis and hydrolysis of fructose-2,6-bisphosphate (Fru-2,6-P2). By directly binding with PFKFB2, linc00092 promotes ovarian cancer metastasis by altering glycolysis and sustaining the local supportive function of cancer-associated fibroblasts (CAFs) one of the most abundant cell components in the tumor microenvironment, which promotes carcinogenesis and cancer progression in different cancer cell types [
46]. miR-17-3p belongs to the polycistronic miR-17-92 cluster, which could associate with c-Myc, a well-studied oncogenic transcription factor showing pivotal promoting effects on cellular glycolysis [
47]. miR-17-3p, which targets GCASPC (gallbladder cancer-associated suppressor of pyruvate carboxylase), can suppress pyruvate carboxylase-dependent cell proliferation in gallbladder cancer by binding and destabilizing the pyruvate carboxylase (PC) protein [
48]. NRCP (lncRNA ceruloplasmin) can function as an intermediary molecule by connecting STAT1 to RNA polymerase II, which leads to upregulation of the key glycolysis enzyme glucose-6-phosphate isomerase (GP6I) and thus promotes glycolysis and cancer progression [
49]. Pyruvate kinase M2 (PKM2) is essential for glucose metabolism, cell proliferation, cell migration, and tumor angiogenesis because dimeric PKM2 diverts glucose metabolism towards anabolism through aerobic glycolysis [
50,
51]. The lncRNA CUDR is well known to be involved in tumorigenesis. Acting as a sponge cushion linking SET1A and pRB1, CUDR increases the expression of HULC, β-catenin, TERT, and c-Myc in human liver cancer stem cells, thus initiating stem cell malignant transformation [
52‐
54] in a metabolic paradigm; however, CUDR can form a complex with p53 to promote hepatocarcinogenesis by transcriptionally activating PKM2 [
55]. Our recent work revealed that FEZF1-AS1 enhances glycolysis through binding and increasing the stability of PKM2 in CRC cells [
56]. Hexokinase catalyzes the first irreversible step of glucose metabolism, thereby producing glucose-6-phosphate through the ATP-dependent phosphorylation of glucose [
57]. In bladder carcinoma, lncRNA UCA1 is overexpressed and promotes glycolysis by upregulating hexokinase 2 (HK2), which promotes aerobic glycolysis and acts as the key indicator of the Warburg effect [
58,
59]. LncRNA PVT1 promotes glucose metabolism in osteosarcoma by inhibiting miR-497/HK2 signaling through a competing endogenous RNA (ceRNA) mechanism [
60].
The let-7/Lin28 pathway plays a central role in mammalian glucose metabolism [
61]. Lin28 promotes malignancy by blocking the biogenesis of tumor-suppressive let-7 and by derepressing the expression of oncogenic lncRNA—H19 [
62]. Moreover, H19 can act as a ceRNA to sponge let-7 and upregulates Lin28 expression in breast cancer cells; in turn, this induction of Lin28 expression further restricts let-7 function [
62]. In addition, by directly binding to let-7, H19 can decrease let-7 availability and suppress the insulin pathway [
63,
64]. Taken together, these findings suggest that H19, let-7, and Lin28 may form a glucose metabolism-related double-negative feedback loop in breast cancer cells.
Lipids are a class of water-insoluble molecules that include triglycerides, phospholipids, sterols, and sphingolipids. The main structural components of biological membranes include phospholipids, sterols, and sphingolipids, whereas triglycerides provide energy storage. Lipids not only play a pivotal role in metabolic processes but also act as signaling molecules [
65]. Similar to glucose metabolism, aberrant alterations in lipid metabolism have also been observed in cancer cells [
66]. Regardless of the concentration of extracellular lipids, the main synthetic pathway of FAs is de novo synthesis. Instead of increase glucose uptake, certain tumor cells could utilize increase lipid oxidation as their main energy source. For example, malignant prostate cells are characterized by a low rate of glucose uptake but a high FA intake [
67].
As master regulators of hepatic lipid homeostasis, sterol regulatory element binding proteins (SREBPs) play extensive roles in lipid metabolism. Mammals have three SREBPs (-1a, -1c, and -2), of which SREBP-1a and SREBP-1c preferentially activate the genes for FA synthesis, and SREBP-2 activates the cholesterol synthesis genes [
68]. LncHR1 was found to decrease lipid metabolism by repressing the SREBP-1c promoter activity and FA synthase (FAS), resulting in decreased accumulation of oleic acid-induced hepatic cell triglyceride (TG) and lipid droplet (LD) in the Huh7 human hepatoma cell line [
69]. FA-binding proteins (FABP), as indispensable carriers of FA uptake and transport, have been proven to be critical central regulators of FA metabolism [
70]. FABP5 is a member of the FABP family and exhibits high-affinity binding to long-chain FAs. LncRNA LNMICC can recruit the nuclear factor NPM1 to the promoter of FABP5, thus reprogramming FA metabolism and promoting lymph node metastasis in cervical cancer [
71].
Acyl-CoA synthase long-chain (ACSL) family members catalyze the initial step in cellular long-chain FA metabolism in mammals; ACSL1, one of the major isoforms of the ACSL family, can increase the uptake of FAs in hepatoma cells and can be regulated by the transcriptional factor PPARα [
72‐
74]. HULC is the first lncRNA found to be specifically overexpressed in hepatocellular carcinoma (HCC) [
75]. In hepatoma cells, HULC suppresses miR-9 targeting PPARα silencing by eliciting the methylation of CpG islands in the miR-9 promoter, and PPARα activates ACSL1 transcription. In this case, HULC stimulates the accumulation of intracellular triglycerides and cholesterol through the miR-9/PPARα/ACSL1 signaling pathway in hepatoma cells [
76].
Fatty liver is an early manifestation of various liver toxicities and is not directly related to the occurrence of primary liver cancer. However, some of the etiologies of fatty liver, such as alcohol, malnutrition, drugs, and toxic damage, are pathogens of both fatty liver disease and liver cancer; therefore, fatty liver and hepatic cancer are often intertwined and share a common molecular regulatory mechanism. LncRNA has been potentially implicated in adipogenesis. Peroxisome proliferator-activated receptor-γ (PPARγ) is a master transcriptional regulator of adipogenesis. Insulin influences adipocyte differentiation through the regulation of MAPKs, including ERK1/2 (p44/p42), p38 and c-Jun amino-terminal kinase (JNK), each of which can regulate adipogenesis [
77]. LncRNA-SRA (steroid receptor RNA) functions as an RNA coactivator for nonsteroid nuclear receptors and contributes to adipogenesis and insulin sensitivity via regulating PPARγ and P38/JNK phosphorylation [
77,
78], and SRA knockout downregulates the size of adipocytes and improves glucose tolerance by protecting against high-fat diet-induced obesity and fatty liver [
79]. We speculated that the SRA-PPARγ-P38/JNK pathway may also be implicated in HCC-related lipid metabolism rearrangement.
Lipin 2 is an enzyme that converts phosphatidate to diacylglycerol (DAG), and diacylglycerol O-acyltransferase 2 (DGAT2) is an enzyme involved in the conversion of DAG to triacylglycerol. LncRNA SPRY4-IT1 expression is low in normal human melanocytes but elevated in melanoma cells. By directly binding with lipin 2, SPRY4-IT1 downregulates the expression of DGAT2, acyl carnitine, fatty acyl chains, and triacylglycerol, thereby leading to cellular lipotoxicity and functioning as an oncogene in human melanoma cells, which provides novel insight into the mechanisms by which extranuclear processing of lncRNAs contributes to lipid metabolism [
80].
In addition to the rearrangement of glucose metabolism, tumor cells also exhibit accelerated glutamine intake and glutaminolysis. Recent work has shown that TUG1 increased glutamine metabolism and increased tumorigenic potential by functioning as an endogenous competing RNA (ceRNA), antagonizing miR-145 and indirectly upregulating sirtuin 3 (Sirt3) and glutamate dehydrogenase (GDH) expression, which provides evidence for its pivotal role in intrahepatic cholangiocarcinoma (ICC) [
81]. Reactive oxygen species (ROS), as by-products of cell metabolism, can induce genetic and epigenetic alterations in human carcinogenesis [
82]. Tumor cells depend for their survival not only on glycolysis but also on glutamine metabolism [
11‐
13]. For instance, glutamine metabolism plays a key role in maintaining redox balance and ROS levels in tumor cells [
83], and glutamine can be converted to glutamate, a precursor of glutathione, by glutaminase 2 (GLS2, a GLS enzyme catalyzing the conversion of glutamine to glutamate) during ROS-induced stress [
84].
The c-Myc family are pivotal glutamine metabolism regulators that regulate the intracellular transposition of glutamate and promote the conversion of glutamine to glutamate [
17,
85]. In colorectal cancer, by suppressing the expression of β-catenin and thereby decreasing c-Myc expression, the lncRNA N-Myc downstream-regulated gene 2 (NDRG2) could inhibit glycolysis, glutaminolysis, and thus cancer growth [
86]. Previous data showed that UCA1 plays a tumor suppressor role by reducing the expression level of c-Myc in esophageal squamous cell carcinoma [
87]. Moreover, in bladder cancer cells, by acting as a miR-16 sponge and upregulating the expression of miR-16 targeting GLS2, UCA1 contributes to glutamine metabolism and represses ROS formation in bladder cancer [
32]. These reports reveal that UCA1 may implement its role in glutamine metabolism by multiple mechanisms.
Functions of lncRNA and mitochondria
In eukaryotic cells, mitochondria are critical hubs for the integration of several key metabolic processes (Fig.
2). To maintain homeostasis, the genome produces specific lncRNA nucleic acids and proteins to coordinate the intense cross-talk between the mitochondria and the nucleus. Currently, the concept of regulation driven by lncRNAs is extending from the nuclear and cytosolic compartments to the mitochondria. Based on the discoveries that (i) the mitochondrial genome can encode lncRNAs [
88,
89] and (ii) lncRNAs may be transcribed in the nucleus but reside in the mitochondria [
90‐
92], a role for mitochondrial lncRNAs in the regulation of mitochondrial functions was suggested.
The first reported human mitochondrial-encoded long noncoding RNAs are SncmtRNA, a long chimeric transcript containing an inverted repeat (IR) of 820 nt covalently bound to the 5′ terminus of the mitochondrial 16S ribosomal RNA, and its two antisense transcripts (ASncmtRNA-1 and ASncmtRNA-2). All three lncRNAs are exported from the mitochondria to the nucleus and can be expressed both in normal proliferating cells and in tumor cells. Notably, both antisense transcripts are universally downregulated in cancer cells [
88]. ASncmtRNA knockdown induces tumor cell apoptosis by inhibiting the expression of survivin, a member of the inhibitor of apoptosis (IAP) family, suggesting that ASncmtRNAs may take part in mitochondrial retrograde signaling [
93]. In addition, although little is known regarding their potential function, several mitochondrial-encoded lncRNAs have been identified [
89,
94] and could provide a new paradigm for understanding mitochondrial function.
Evidence is now emerging that several nuclear-encoded lncRNAs can execute regulatory roles in mitochondria. The lncRNA SAMMSON is predominantly localized to the cytoplasm of human melanoblasts and melanoma cells [
91]. SAMMSON depletion in melanoma cells decreases the mitochondrial targeting of p32, a mitoribosome assembly and mitochondrial protein synthesis regulator, and attenuates mitochondrial protein synthesis [
95], which ultimately triggers cell apoptosis. ARL2 is present in the inner membrane space of mitochondria and is an activator of ATP/ADP transporters. UCA1 can act as a competing endogenous RNA (ceRNA) and contributes to ARL2-induced mitochondrial activity by inhibiting miR-195-5p in bladder cancer [
96]. The peroxisome proliferator-activated receptor γ (PPARγ) coactivator α (PGC-1α) is encoded by Ppargc1a and is a well-characterized transcriptional coactivator that plays an integral role in maintaining energy homeostasis and mitochondrial biogenesis in response to a myriad of nutrient and hormonal signals [
97]. PGC-1α enhances its own transcription via an autoregulatory loop [
98]. By binding directly to an R/S-rich region of the CTD of PGC-1α, the lncRNA TUG1 recruits PGC-1α protein to the Ppargc1a promoter, which enhances PGC-1α expression, leading to increased mitochondrial content, enhanced mitochondrial respiration, increased cellular ATP levels, and reduced mitochondrial ROS [
99]. Bcl2 plays a key role in the mitochondrial pathway and regulates cell death by controlling the permeability of the mitochondrial membrane [
100]. Tumor-suppressive MEG3 can induce the apoptosis of renal cell carcinoma cells by downregulating Bcl2 expression and thereby stimulating the mitochondrial pathway [
101]; similarly, blockage of oncogenic HOTAIR induces mitochondrial calcium uptake 1 (MICU1)-dependent cell death and changes mitochondrial membrane potential by regulating mitochondrial related cell death pathway (Bcl-2, BAX, caspase-3, cleaved caspase-3, cytochrome c) [
102]. LncRNA NDRG2 prevents p53 from entering the nucleus and promotes the accumulation of P53 in the mitochondria by increasing the half-life of Bad, thus promoting apoptosis in a p53-dependent manner in breast cancer cells [
103]. Considering these pieces of evidence, we concluded that lncRNAs are required for mitochondrial bioenergetics and thus for the maintenance of mitochondrial energy homeostasis.