Involvement of Long Non-Coding RNAs in Glucose Metabolism in Cancer

Simple Summary Long non-coding RNAs (lncRNAs) are a heterogenous group of transcripts that regulate various cellular functions. They are implicated in all hallmarks of cancer, including metabolic alterations. Through the modulation of expression of oncogenic or tumor-suppressive genes, alteration of various signaling pathways, protein stability, and upregulation of metabolic enzymes, lncRNAs enhance glucose uptake in cancer and, thus, favor cancer progression. These transcripts represent crucial regulators of cancer glucose metabolism and, as such, they are potential clinical biomarkers and therapeutic targets. This review aims to provide an overview of the lncRNAs involved in cancer glucose metabolism and summarizes their underlying molecular mechanisms. Abstract The rapid and uncontrolled proliferation of cancer cells is supported by metabolic reprogramming. Altered glucose metabolism supports cancer growth and progression. Compared with normal cells, cancer cells show increased glucose uptake, aerobic glycolysis and lactate production. Byproducts of adjusted glucose metabolism provide additional benefits supporting hallmark capabilities of cancer cells. Long non-coding RNAs (lncRNAs) are a heterogeneous group of transcripts of more than 200 nucleotides in length. They regulate numerous cellular processes, primarily through physical interaction with other molecules. Dysregulated lncRNAs are involved in all hallmarks of cancer including metabolic alterations. They may upregulate metabolic enzymes, modulate the expression of oncogenic or tumor-suppressive genes and disturb metabolic signaling pathways favoring cancer progression. Thus, lncRNAs are not only potential clinical biomarkers for cancer diagnostics and prediction but also possible therapeutic targets. This review summarizes the lncRNAs involved in cancer glucose metabolism and highlights their underlying molecular mechanisms.


Introduction
Cancers are characterized by uncontrolled and rapid cellular proliferation. To satisfy the accompanying increased demand for energy, cancer cells have to reprogram their metabolism, especially glucose metabolism [1,2]. Normal cells commonly acquire energy via glycolysis in the cytosol and oxidative phosphorylation in the mitochondria, which produces more ATP per molecule of glucose. When oxygen is deficient, cells primarily rely on glycolysis rather than on oxygen-consuming mitochondrial oxidative phosphorylation [3]. However, cancer cells favor glycolysis even in the presence of oxygen. This phenomenon is known as aerobic glycolysis or the Warburg effect [4]. Despite being known for decades, it was only recently acknowledged as a hallmark of cancer [5]. Cancer cells compensate for the net energy loss of glycolysis by an increased glucose uptake and eventual lactate production. Lactate lowers the surrounding pH, which additionally aids cancer invasion and Multiple studies have documented an aberrant lncRNA expression in various cancers where they act as oncogenes or tumor suppressors [19][20][21]. A few of these contributions to cancers are induced by lncRNAs via their ability to regulate glucose metabolism. They upregulate metabolic enzymes, disturb metabolic signaling pathways and modulate the expression of oncogenic or tumor-suppressive genes ( Figure 2). In addition to potentially Multiple studies have documented an aberrant lncRNA expression in various cancers where they act as oncogenes or tumor suppressors [19][20][21]. A few of these contributions to cancers are induced by lncRNAs via their ability to regulate glucose metabolism. They upregulate metabolic enzymes, disturb metabolic signaling pathways and modulate the expression of oncogenic or tumor-suppressive genes ( Figure 2). In addition to potentially being useful as clinical biomarkers for cancer diagnostics and prediction, lncRNAs are also increasingly being considered as potential therapeutic targets [22]. being useful as clinical biomarkers for cancer diagnostics and prediction, lncRNAs are also increasingly being considered as potential therapeutic targets [22].
The aim of this review is to provide an overview of the lncRNAs involved in cancer glucose metabolism. Additionally, we summarize the molecular mechanisms by which they exert these effects.

Methods
This review article is based on a literature review using the PubMed database. The following terms were used to search for the articles: 'glucose metabolism', 'long-non-coding RNA', 'lncRNA', 'cancer'. Cancer studies in which the involvement of lncRNA in glucose metabolism was confirmed were used for further evaluation and were incorporated into this review.

Results
A total of 63 articles meeting the entry criteria is included in this review article. The main findings are interpreted through two main sections. The first section summarizes the pathophysiological processes of cancer regulated by lncRNAs and their influence on glucose metabolism. The second section summarizes the general findings according to the types of cancers.

LncRNAs Regulates Pathophysiological Processes in Cancer Via the Influence of Glucose Metabolism
LncRNAs are dysregulated in various pathophysiological processes. A few of these processes include interactions with the tumor microenvironment and drug resistance.
Numerous studies have documented altered expression of various lncRNAs under hypoxic conditions. Hypoxic stress, in turn, increases the rates of glucose consumption and lactate production [23,24]. For example, lncRNA AC020978 is upregulated in nonsmall cell lung cancer (NSCLC) under glucose deprivation and hypoxia [25]. Similarly, the lncRNA HOXA transcript at the distal tip (HOTTIP) promotes glycolysis under hypoxic conditions via the miR-615-3p/HMGB3 axis in NSCLC cells [26]. In ovarian cancer, gastric carcinoma high expressed transcript 1 (GHET1) interacts with the E3 ubiquitin lig- The aim of this review is to provide an overview of the lncRNAs involved in cancer glucose metabolism. Additionally, we summarize the molecular mechanisms by which they exert these effects.

Methods
This review article is based on a literature review using the PubMed database. The following terms were used to search for the articles: 'glucose metabolism', 'long-non-coding RNA', 'lncRNA', 'cancer'. Cancer studies in which the involvement of lncRNA in glucose metabolism was confirmed were used for further evaluation and were incorporated into this review.

Results
A total of 63 articles meeting the entry criteria is included in this review article. The main findings are interpreted through two main sections. The first section summarizes the pathophysiological processes of cancer regulated by lncRNAs and their influence on glucose metabolism. The second section summarizes the general findings according to the types of cancers.

LncRNAs Regulates Pathophysiological Processes in Cancer Via the Influence of Glucose Metabolism
LncRNAs are dysregulated in various pathophysiological processes. A few of these processes include interactions with the tumor microenvironment and drug resistance.
Numerous studies have documented altered expression of various lncRNAs under hypoxic conditions. Hypoxic stress, in turn, increases the rates of glucose consumption and lactate production [23,24]. For example, lncRNA AC020978 is upregulated in non-small cell lung cancer (NSCLC) under glucose deprivation and hypoxia [25]. Similarly, the lncRNA HOXA transcript at the distal tip (HOTTIP) promotes glycolysis under hypoxic conditions via the miR-615-3p/HMGB3 axis in NSCLC cells [26]. In ovarian cancer, gastric carcinoma high expressed transcript 1 (GHET1) interacts with the E3 ubiquitin ligase von Hippel-Lindau (VHL). This consequently prevents the VHL-mediated degradation of HIF1α. Increased levels of HIF1α promote the glucose uptake and lactate production in ovarian cancer cells [27]. In addition, the HIF1α/lncRNA Retinoic Acid Early Transcript 1K (RAET1K)/miR-100-5p axis modulates hypoxia-induced glycolysis in hepatocellular carcinoma (HCC) cells and affects HCC progression [28].
Moreover, extracellular cytokines may increase the expression of lncRNAs. Urothelial carcinoma-associated 1 (UCA1) is upregulated by TGF-β1 in HCC. UCA1 then upregulates metabolic enzymes and increases glucose uptake and lactate production [29]. Interestingly, even microorganisms may modify glucose metabolism in cancer via lncRNAs. Fusobacterium nucleatum, a member of the normal flora in the oral cavity, activates lncRNA ENO1-IT1 transcription that eventually induces glucose metabolism in colorectal cancer (CRC) [30].
Furthermore, drug resistance is one of the biggest challenges in cancer treatment. Understanding the contributing factors is of the utmost importance in achieving better clinical outcomes [31]. Emerging studies correlate many lncRNAs with drug resistance across different types of cancers. UCA1 is upregulated in acute myeloid leukemia (AML) following adriamycin (ADR)-based chemotherapy. It contributes to HIF1α-dependent glycolysis in AML [32]. This lncRNA is also upregulated in radioresistant cervical cancer cell lines and promotes glycolysis. In cytarabine-resistant AML cell lines, HOX antisense intergenic RNA myeloid 1 (HOTAIRM1) increases glucose consumption, lactate production and cellular proliferation [33]. In addition, lncRNA H19 overexpression in ginsenoside 20(S)-Rg3-treated ovarian cancer cells increases glucose consumption, lactate production and pyruvate kinase isozyme M2 (PKM2) expression [34]. Another study proved increased glucose consumption and lactate secretion in cetuximab-resistant CRC cells, suggesting that glucose metabolism might be involved in cetuximab resistance. In the resistant cell lines, LINC00973 was upregulated [35].

Gastrointestinal Cancers
Gastrointestinal cancers rank among the most commonly diagnosed cancers worldwide. In 2018, almost six million new cases were reported and around four million people died [36]. Moreover, these cancers are among the most commonly studied for the roles of lncRNAs [37][38][39]. The gastrointestinal tract comprises the organs that mediate digestion, suggesting that altered glucose metabolism may be an important factor in the development and progression of cancers of this system [40]. See Table 1 for a summary of lncRNA involvement in glucose metabolism in gastrointestinal cancers.

Colorectal Cancer
A common lncRNA-induced disarragement of glucose metabolism in colorectal cancer (CRC) is mediated via the c-MYC oncogene. Many genes that are important for cell growth and cancer progression are targeted by c-MYC including those that regulate metabolism [41]. Glycolysis-associated lncRNA of colorectal cancer (GLCC1), also referred to as AF339830, is an oncogenic lncRNA in CRC. It is associated with poor overall survival (OS) of CRC patients (p = 0.0023). A higher GLCC1 expression leads to increased celllular proliferation and an upregulated glycolysis pathway while experimental downregulation results in a significant reduction of cellular proliferation and tumor growth in mouse models. In addition, GLCC1 stabilizes c-MYC and prevents its degradation by combining it with a heat shock protein 90 (HSP90) chaperon. This further increases the transcriptional level of lactate dehydrogenase A (LDHA), which then activates glycolytic metabolism. It has also been found that glucose starvation significantly increases GLCC1 expression, suggesting that GLCC1 may be a glucose starvation-induced oncogenic lncRNA in CRC [42]. The same physicial interaction with c-MYC and resulting effects have been observed for LINC00504 [43]. Similarly, oncogenic long intergenic non-coding RNA for IGF2BP2 Stability (LINRIS) is important for glycolysis maintainance in CRC. It interacts with insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) and blocks its degradation through the ubiquitination-autophagic pathway. In turn, c-MYC, a downstream target of IGF2BP2, is stabilized. Consequently, the expression of MYC-related metabolic enzymes glucose trasporter 1 (GLUT-1), pyruvate kinase isozyme M2 (PKM2) and LDHA is increased [44].
Wu and colleagues [35] investigated the underlying differences between cetuximabresistant and cetuximab-sensitive CRC cells. They proved an increased glucose consumption and lactate secretion in cetuximab-resistant cells, suggesting that glucose metabolism might be involved in cetuximab resistance. In addition, lncRNA LINC00973 was upregulated in the resistant cell lines. Upon siRNA-mediated LINC00973 downregulation, the resistant cells exhibited increased apoptosis, reduced cell viability and decreased glucose consumption and lactate production [35].
Huang et al. [49] confirmed the upregulation of lncRNA FEZF1 antisense RNA 1 (FEZF1-AS1) in two expanded CRC cohorts. They revealed that FEZF1-AS1 expression is associated with CRC cell proliferation, metastasis and a poor OS (logrank p = 0.004) and DFS (logrank p = 0.019). Moreover, they found that FEZF1-AS1 binds to cytoplasmic and nuclear PKM2 protein thereby increasing its stability and promoting its activity. Cytoplasmic PKM2 promotes pyruvate kinase activity and lactate production (aerobic glycolysis), whereas nuclear PKM2 acts as a protein kinase and activates STAT3 signaling. A multivariate analysis showed that FEZF1-AS1 expression is an independent risk factor for the survival of patients with CRC (HR, 2.240; 95% CI, 1.028-4.878; p = 0.042) [49].
Wang and colleagues [28] demonstrated that the HIF1α/lncRNA Retinoic Acid Early Transcript 1K (RAET1K)/miR-100-5p axis modulates hypoxia-induced glycolysis in HCC cells and affects HCC progression. The expression of lncRNA RAET1K, HIF1α and LDHA is upregulated in HCC tissue specimens while the miR-100-5p expression level is decreased. Mechanistically, RAET1K downregulates the expression of miR-100-5p by acting as a sponge while HIF1α binds the promoter region of the RAET1K and activate its transcription. RAET1K silencing significantly suppressed HCC cell proliferation and invasion. It also suppressed the hypoxia-induced increase in lactate concentration and glucose uptake while miR-100-5p inhibition reversed the effects of RAET1K silencing on hypoxia-induced glycolysis in HCC cells [28]. Upregulated lncRNA five prime to Xist (Ftx) is associated with aggressive clinicopathological features of HCC. In addition, Ftx enhances the activity and expression of key enzymes in glucose metabolism GLUT-1 and GLUT-4. Mechanistically, Ftx directly regulates the transcriptional and post-transcriptional expression of PPARγ. The PPARγ pathway is responsible for the Ftx-induced aerobic glycolysis in HCC [53].
It has been shown that TGF-β1 upregulates the expression of lncRNA urothelial carcinoma-associated 1 (UCA1) in HCC, which in turn significantly increases the expression level of HK2. Consequently, lactate production, glucose uptake and ATP production are increased while the OS is decreased (p = 0.0152) [29]. LncRNA SOX2OT promotes glucose metabolism by PKM2, HK2 and LDHA activation and increases the metastatic potential of HCC. SOX2OT physically binds to miR-122-5p, which also has a PKM2 targeting site and contributes to the PKM2 induction [58]. LncRNA DEAD/H box protein 11 antisense RNA 1 (DDX11-AS1) directly binds to tumor-suppressive miR-195-5p, thus allowing MACC1, a key regulator of the hepatocyte growth factor-HGF receptor (HGFR) pathway, to be overexpressed in HCC. As a result of DDX11-AS1 overexpression, glucose consumption, lactate production, cellular proliferation, invasion and migration are increased [57].
Yu and colleagues [54] investigated the correlation between HCC and blood glucose dysregulation. HCC cells treated with a high glucose concentration were shown to have an increased expression of miR-483-3p and a decreased expression of lncRNA maternally expressed gene 3 (MEG3). Both of them led to suppressed endoplasmic reticulum protein 29 (ERp29) expression, which resulted in an increased HCC cell proliferation and migration. They found that MEG3 mediates protective effects via binding to miR-483-3p. When MEG3 is downregulated, overexpressed miR-483-3p suppresses ERp29 expression. Normally, ERp29 decreases cell proliferation and prevents epithelial-mesenchymal transition [54].

Pancreatic Cancer
LncRNA HOTAIR is overexpressed in patients with pancreatic adenocarcinoma. HO-TAIR alters cancer cell energy metabolism in pancreatic adenocarcinoma by the upregulation of HK2. This leads to the enhancement of tumor cell proliferation, glucose uptake, increased ATP and lactate production [61].

Esophageal Cancer
Zhao et al. [62] investigated the function of long intergenic non-protein coding RNA 184 (LINC00184) on glycolysis and mitochondrial oxidative phosphorylation of esophageal cancer cells. They found that highly expressed LINC00184 increases esophageal cancer cell proliferation, migration, invasion and colony formation. LINC00184 recruits DNA methyltransferase 1 (DNMT1) to tumor-suppressive phosphatase and the tensin homolog (PTEN) promotor region. Silenced PTEN, via Akt phosphorylation, leads to increased glycolysis and decreased mitochondrial oxidative phosphorylation [62]. Another lncRNA that was found to play a role in esophageal cancer is the lncRNA UCA1. UCA1 mediates oncogenic effects by regulating glucose metabolism in esophageal cancer. It significantly suppresses the degradation of HK2 by sponging miR-203. Upregulated UCA1 increases the glucose uptake, lactate output and extracellular acidification rate (ECAR) value [63].

Gallbladder Cancer
Sun and colleagues [64] reported that lncRNA plasmacytoma variant translocation 1 (PVT1) acts as an oncogenic lncRNA in gallbladder cancer (GBC) by sponging and repressing miR-143, allowing HK2 to be overexpressed. The upregulation of HK2 is responsible for the higher cellular glucose consumption and lactate production, which gives GBC cells an edge for proliferation, migration and invasion [64]. In addition, PVT1 has been found to be overexpressed in multiple other cancers including CRC, non-small cell lung cancer (NSCLC) and pancreatic cancer [74][75][76]. However, its implications in glucose metabolism disruption in these cancer entities has yet to be investigated.

Genitourinary Cancers
Genitourinary (GU) cancers comprise of a group of cancers in urinary and male reproductive systems [77]. They affect a large number of patients each year with prostate cancer being the most commonly diagnosed cancer and the second leading cause of death in males [78]. Table 2 provides and overview of lncRNA involvement in glucose metabolism in genitourinary cancers. Kidney Cancer Kidney-specific lncRNA FoxO-induced long non-coding RNA 1 (FILNC1) is downregulated in renal cell carcinoma correlating with poor clinical outcomes. Upon glucose starvation, the transcription factor FoxO upregulates FILNC1 expression. In turn, FILNC1 interacts with c-MYC mRNA-binding protein (AUF1), which prevents the interaction of AUF1 with c-MYC mRNA. This leads to the downregulation of c-MYC protein levels. However, in renal cancer, this pathway is altered. FILNC1 is downregulated leading to increased c-MYC protein levels thereby increasing the glucose uptake, lactate production and tumor development [79].

Bladder Cancer
Duan et al. [80] observed that the lncRNA cancer susceptibility candidate 8 (CASC8) is significantly downregulated in bladder cancer and established its association with an advanced stage of bladder cancer. Normally, CASC8 binds to the fibroblast growth factor receptor 1 (FGFR1), which in turn prevents FGFR1-mediated LDHA phosphorylation. Consequently, the conversion of pyruvate into lactate is attenuated, glycolysis is reduced and bladder cancer cell proliferation is slowed down [80]. As already observed in HCC and esophageal cancers, lncRNA UCA1 also promotes glycolysis in bladder cancer cells. It regulates glycolysis by upregulating HK2 expression through mTOR and its downstream effector STAT3, which is a direct transcriptional activator for HK2 [81]. An additional mechanism of positive HK2 regulation is mediated through miR-143 downregulation by the active mTOR [82].

Prostate Cancer
Prostate cancer gene expression marker 1 (PCGEM1), a lncRNA highly associated with prostate tumors, significantly induces genes involved in multiple metabolic pathways such as aerobic glycolysis, pentose phosphate shunt and NADPH generation used for redox homeostasis. Mechanistically, PCGEM1 binds directly to the target promoter of c-MYC where it functions as a coactivator and mediates enhanced c-MYC transcription [83].

Female Reproductive System Cancers Ovarian Cancer
Sood et al. [84] investigated the role of lncRNA ceruloplasmin (NRCP) in ovarian cancer metabolism. They found that NRCP is highly upregulated in ovarian tumors while its experimental knockdown leads to a decreased glycolysis and an increased mitochondrial respiration in cancer cells (Table 3). This, in turn, results in significantly increased cancer cell apoptosis and decreased cell proliferation. Mechanistically, NRCP acts as an intermediate binder between STAT1 and RNA polymerase II thereby increasing their activities. This leads to an elevated expression of the downstream target genes glucose-6-phosphate isomerase (GPI), aldolase A (ALDOA) and aldolase C (ALDOC) [84]. Furthermore, lncRNA gastric carcinoma high expressed transcript 1 (GHET1) is overexpressed in ovarian cancers and it is positively correlated with the tumor size and metastasis in patients. The overexpression of GEHT1 promotes proliferation and colony formation of ovarian cancer cells. GHET1 interacts with the E3 ubiquitin ligase von Hippel-Lindau (VHL), which consequently prevents the VHL-mediated degradation of HIF1α. Increased levels of HIF1α promote the glucose uptake and lactate production of ovarian cancer cells [27]. The important roles of lncRNAs in the regulation of HIF1α in cancer have been demonstrated previously [23]. It was observed that lncRNA H19 overexpression in ginsenoside 20(S)-Rg3-treated ovarian cancer cells enhances glucose consumption, lactate production and PKM2 expression. H19 directly sponges miR-324-5p to enhance the Warburg effect. Unaffected miR-324-5p inhibits PKM2 and negatively regulates glucose uptake and lactate production in ovarian cancer cells and inhibits cell proliferation [34]. Table 3. Examples of lncRNAs implicated in glucose metabolism alteration in female reproductive system cancers.

Upregulated in ovarian cancers
Interacts with the E3 ubiquitin ligase von Hippel-Lindau (VHL); prevents VHL-mediated HIF1α-degradation; promotes glucose uptake and lactate production [27] H19 Upregulated in ginsenoside 20(S)-Rg3-treated ovarian cancers Sponges miR-324-5p; upregulates PKM2; increases glucose uptake and lactate production [34] UCA1 Upregulated in radioresistant cervical cancer Upregulates HK2 [85] Cervical Cancer Yao and colleagues [85] showed that lncRNA UCA1 has increased expression levels in radioresistant cervical cancer cell lines and promotes glycolysis. In addition, they found that this mechanism is regulated by the HK2 enzyme. These findings suggest that UCA1 plays an important role in the regulation of radioresistance in cervical cancer via the HK2/glycolytic pathway [85].

Breast Cancer
Lin and colleagues [86] demonstrated that lncRNA LINC00538 (YIYA) promotes cancer glycolysis, cell proliferation and tumor growth in breast cancer (Table 4).
Mechanistically, YIYA associates with the cytosolic cyclin-dependent kinase CDK6. It regulates the CDK6-dependent phosphorylation of the fructose bisphosphatase PFK2 (PFKFB3) in a cell cycle-independent manner and the catalysis of glucose 6-phosphate to fructose-2,6-bisphosphate/fructose-1,6-bisphosphate. Both lncRNA YIYA and CDK6 are required to maintain enhanced glycolysis in breast cancer [86]. Another study proved that upregulated lncRNA breast cancer anti-estrogen resistance 4 (BCAR4) in triple negative breast cancer is transcriptionally targeted by Yes-associated protein (YAP) and it is required for YAP-promoted glycolysis through GLI2-dependent Hedgehog signaling. YAP is normally inhibited by the tumor-suppressive Hippo pathway, which is commonly disregulated in many cancers [87]. BCAR4 associates with the Hedgehog signalling effector GLI2 and promotes the transcription of glycolytic activators HK2 and PFKFB3. The individual or simulanteous upregulation of BCAR4 and GLI2 results in increased glucose uptake and lactate production. The overexpression of YAP (p = 0.0166) and BCAR4 (p = 0.0173) correlates with a poor recurrence-free survival (RFS) for breast cancer patients [88]. LINC00346 is also overexpressed in breast cancer cells. Its experimental knockdown results in reduced cell proliferation and glycolysis as well as induced apoptosis through the upregulation of miR-148a/b, which is a direct target of LINC00346. The lower glycolysis rate is due to a repressed GLUT-1 expression [89].

Hematologic Cancer
Wang et al. [90] found that lncRNA antisense non-coding RNA at the INK4 locus (ANRIL) is overexpressed in acute myeloid leukemia (AML) patients and promotes disease development and progression via the modulation of glucose metabolism. This lncRNA is commonly involved in multiple solid tumors [91] ( Table 5). The authors found that ANRIL increases AML cell survival via the AdipoR1 pathway, which is an important regulator in cell senescence and metabolism including the Warburg effect. ANRIL and AdipoR1 upregulation results in the increased expression of GLUT-1, which facilitates the transportation of glucose across the plasma membrane, and LDHA, the enzyme that converts pyruvate to lactate. In addition, AdipoR1 upregulates AMPK and SIRT1, the main regulators of cell senescence and cell metabolism. Thus, they are important targets in AML treatment [90]. Moreover, lncRNA in non-homologous end joining (NHEJ) pathway 1 (LINP1) is significantly overexpressed in AML patients. It promotes the malignant phenotype of AML cells and stimulates glucose metabolism [92]. Previous studies have confirmed that LINP1 functions as a scaffold for interaction with several important regulators in NHEJ-mediated DNA repair [93,94]. LINP1 upregulates the expression levels of GLUT-1 and LDHA by upregulating HNF4α, which in turn activates the AMPK/WNT5A signaling pathway. The knockdown of LINP1 expression remarkably suppresses the glucose uptake and AML cell maintenance [92]. Oncogenic lncRNA UCA1 is also upregulated in AML following adriamycin (ADR)-based chemotherapy. Mechanistically, UCA1 acts as a ceRNA of miR-125a and directly binds to it. Consequently, HK2, a target of miR-125a, is upregulated while the miR-125-mediated inhibition of a HIF1α-dependent glycolysis is blocked [32]. HOX antisense intergenic RNA myeloid 1 (HOTAIRM1) is the lncRNA that is highly specific for maturing myeloid cells and is well-known for its implication in the development of AML [95,96]. In cytarabine-resistant AML cell lines, HOTAIRM1 enhances cell viability, reduces apoptosis and enhances glucose consumption and lactate production. These effects are mediated via the activated Wnt/β-catenin pathway [33].
Wang et al. [97] found that lncRNA protein disulfide isomerase family A member 3 pseudogene 1 (PDIA3P) is highly expressed in multiple myeloma and correlates with the OS of patients. They found that PDIA3P regulates multiple myeloma growth and drug resistance through glucose 6-phosphate dehydrogenase (G6PD) and the pentose phosphate pathway (PPP). Specifically, PDIA3P interacts with c-MYC thereby enhancing its transactivation and binding to the G6PD promoter, thus stimulating G6PD expression and PPP flux [97]. Additionally, lncRNA MALAT1 is upregulated in multiple myeloma serums and cells. It is responsible for increased cell viability, invasion and glycolysis. MALAT1 sponges miR-1271-5p, inhibiting its functions. In turn, SRY-Box 13 (SOX13), a miR-1271-5p target, is upregulated [98]. SOX13 is a member of the SRY-related high-mobility group box (Sox) transcription factor family and is known to be involved in the progression of several tumors including glioma [99]. Increases the expression of GLUT-1 and LDAH, upregulates AdipoR1, AMPK and SIRT1 [90] LINP1 Upregulated in AML Increases the expression of GLUT-1 and LDHA; upregulates HNF4α; activates the AMPK/WNT5A signaling pathway [92] UCA1 Upregulated in AML ceRNA of miR-125a; upregulates HK2; blocks HIF1α-dependent glycolysis [32] HOTAIRM1 Upregulated in AML Activates the Wnt/β-catenin pathway; enhances glucose uptake and lactate production [33] PDIA3P Upregulated in multiple myeloma Interacts with c-MYC; upregulates G6PD expression and PPP flux [97] MALAT1 Upregulated in multiple myeloma Targets miR-1271-5p; increases SOX13 expression [98] 3.2.6. Brain Cancers Guo and colleagues [100] observed that the lncRNA X-inactive specific transcript (XIST) is upregulated in glioblastoma cell lines and tissue samples ( Table 6). Knockdown experiments highlighted the importance of this lncRNA in glioblastoma cell viability, invasion, resistance to apoptosis and enhanced glucose metabolism. XIST acts as a ceRNA for miR-126. By sponging miR-126, insulin receptor substrate 1 (IRS1) is upregulated along with the PI3K/Akt pathway. In addition, protein levels of GLUT-1 and GLUT-3 receptors as well as cellular glucose uptake and lactate production are elevated [100]. This lncRNA is also involved in several other cancer entities including bladder cancer, cervical cancer and pancreatic cancer, always exerting its functions via sponging various miRNAs and thereby promoting cancer progression [101][102][103]. However, a potential mechanism of XIST in glucose metabolism disruption in these cancers is yet to be investigated.
The expression level of lncRNA TP53 target 1 (TP53TG1) is significantly higher in human glioma tissues or cell lines compared with normal brain tissue. TP53TG1 is shown to be important in cellular proliferation and migration. It also promotes the upregulation of several glucose metabolism related genes such as glucose-regulated protein 78 (GRP78), isocitrate dehydrogenase 1 (IDH1) and LDHA. Interestingly, these effects are more striking in situations of glucose deprivation than in high glucose conditions [108]. Similarly, increased levels of Metastasis Associated in Colon Cancer 1 Antisense RNA 1 (MACC1-AS1), particularly under glucose deprivation, result in increased cell viability and inhibited apoptosis. High levels of MACC1-AS1 in glioma tissues and cells are associated with a poor prognosis of glioma patients (p = 0.0106). MACC1-AS1 overexpression significantly increases the levels of GLUT-1, HK2, G6PD, MCT1, ATP, lactate and NAPDH. These effects of MACC1-AS1 overexpression were found to be mediated via the AMPK pathway [109].

Osteosarcoma
Yang and colleagues [110] investigated the oncogenic mechanisms of lncRNA taurineupregulated gene 1 (TUG1) in osteosarcoma (Table 7). They reported inhibited glucose consumption, lactate production and cell viability of osteosarcoma cells upon TUG1 knockdown. However, an increased expression of TUG1 markedly increased the expression of HK2 [110]. Similarly, upregulated lncRNA Potassium Voltage-Gated Channel Subfamily Q Member 1 Overlapping Transcript 1 (KCNQ1OT1) facilitates proliferation and decreases the apoptosis of osteosarcoma cells. KCNQ1OT1 contributes to the Warburg effect by stimulating ALDOA expression. KCNQ1OT1 sponges miR-34c-5p, which directly targets and inhibits ALDOA expression [111]. Similar to its effect in GBC, PVT1 upregulation has been observed in osteosarcoma where it is associated with a poor survival of patients (p = 0.011). Glucose uptake, lactate production and the expression of HK2 are all increased in osteosarcoma cells with an overexpression of PVT1 and decreased by PVT1 knockdown [112]. HAND2-AS1 Downregulated in osteosarcoma Decreases GLUT-1 and glucose update [113,114] In contrast, lncRNA heart and neural crest derivatives expressed 2-antisense RNA 1 (HAND2-AS1) has a decreased expression in osteosarcoma compared with normal tissue and functions as a tumor suppressor. The disruption of lncRNA HAND2-AS1 results in osteosarcoma cell proliferation through the alteration of glucose metabolism. It leads to an increased expression of GLUT-1, consequently enhancing glucose uptake and the proliferation of osteosarcoma cell lines. Interestingly, HAND2-AS1 is not associated with metastasis formation [113]. Another study has shown that HAND2-AS1 regulates osteosarcoma metabolism via sequestering fructose-1,6-bisphosphatase 1 (FBP1) from binding to HIF1α thereby increasing the HIF1α expression [114]. Additionally, a tumor-suppressive role of this lncRNA has recently been identified in endometrioid carcinoma that acts via different mechanisms [115]. The potential involvement in glucose metabolism alteration should be investigated.

Melanoma
H19 acts as an oncogenic lncRNA in many human cancers [116,117]. Xu et al. [118] identified its molecular mechanisms in melanoma. They found that H19 acts as a sponge for miR-106a-5p, leading to the upregulation of E2F3 transcription factor expression in melanoma cells. E2F3 promotes melanoma cell glucose metabolism and growth [118].

Lung Cancer
Huang and colleagues [25] proved that lncRNA AC020978, which is upregulated in non-small cell lung cancers (NSCLC) ( Table 8), has a significant correlation with advanced stage and poor clinical outcomes. AC020978 promotes cell growth and induces metabolic reprogramming. It is upregulated under glucose deprivation and hypoxia. Mechanistically, AC020978 directly interacts with PKM2 and enhances the stability of this protein, which is crucial for the Warburg effect. In addition, AC020978 promotes the nuclear translocation of PKM2. It thereby acts as a protein kinase and interacts with many tumor-associated genes to accelerate carcinogenesis including HIF1α, Oct-4, STAT3 and CTNNB1 that encode β-catenin [25]. Likewise, the lncRNA HOXA transcript at the distal tip (HOTTIP) promotes glycolysis under hypoxic conditions via the miR-615-3p/HMGB3 axis in NSCLC cells. Hypoxic stress increases the rates of glucose consumption and lactate production. Glycolysis rate is increased by the substantial increase of HK2 enzyme expression compared with control cells grown in a normoxic environment. In addition, hypoxia increases HOTTIP and high mobility group box 3 (HMGB3) expression while it suppresses miR-615-3p expression. Mechanistically, HOTTIP acts as a molecular sponge for miR-615-3p leading to an increased expression of its target HMGB3 [26]. HMGB3 is a well-known oncogenic member of chromatin-binding proteins that can regulate gene expression in various cancers via transcription factor binding modulation [119][120][121]. Moreover, lncRNA MALAT1 is upregulated in NSCLC tissues and cells. It is responsible for enhanced cell proliferation, colony formation, reduced cell apoptosis in vitro and increased tumor growth in vivo. MALAT1 knockdown decreases glucose consumption and lactate production. It mediates these effects by binding to miR-613 thereby inhibiting its interaction with copper metabolism MURR1 domain-containing 8 (COMMD8) [122]. Research on COMMD8 in cancers is scarce. However, in addition to this research, one more study has shown that the overexpression of COMMD8 mitigates malignant NSCLC features [123]. Another oncogenic lncRNA in NSCLC is brain cytoplasmic RNA 1 (BCYRN1). BCYRN1 induces glycolysis and upregulates the expression levels of PKM2 in NSCLC cells. These effects are mediated by reducing the miR-149 expression levels [124]. LINC00551 has a low expression in lung adenocarcinoma and correlates with a worse OS of lung cancer patients (HR = 0.67, logrank p = 0.0014). It regulates the glycolytic pathway by suppressing glucose uptake and lactate production. Mechanistically, LINC00551 inhibits glycolysis by impairing the c-MYC-mediated transcription of glycolytic enzymes particularly PKM2 [125].

Head and Neck Cancer
LncRNA ANRIL is also highly expressed in patients with nasopharyngeal carcinoma (Table 9). Overexpression is associated with advanced stage cancer, a shorter OS (p = 0.027), DFS (p = 0.033), frequent recurrences, increased cell proliferation and transformation via a stem-like cancer cell induction. ANRIL reprograms glucose metabolism to meet the cancer's increased needs for energy by increasing the glucose uptake. It does that by affecting the mTOR signal pathway, which in turn increases the expression of GLUT-1 and LDHA, essential genes in glucose metabolism [126]. Table 9. Examples of lncRNAs implicated in glucose metabolism alteration in head and neck cancer.

Conclusions
To maintain the characteristics of uncontrolled and accelerated proliferation, cancer cells reprogram their metabolism. This provides cancer with numerous benefits enabling its growth and progression. As glucose is the main source of energy, it is excessively metabolized by cancer cells leading to increased lactate production. Byproducts of altered glucose metabolism are substrates essential for the building of new cellular components and they lead to a lower surrounding pH thereby aiding metastasis formation. Metabolic disarrangement is associated with poor outcomes in certain cancers. A few of the key players of glucose metabolism such as LDAH and PKM2 could be used in patient stratifications and the prediction of the disease outcomes.
LncRNAs are a heterogenous group of transcripts capable of mediating various cellular functions including the regulation of glucose metabolism. Different molecular mechanisms of lncRNAs have been described. Among the most common is the regulation of the expression of metabolic enzymes such as GLUTs, LDAH, PKM2 and HK2. Namely, ANRIL, UCA1, HOTAIR and H19 are a few of the most familiar lncRNAs that target metabolic enzymes. In addition, lncRNAs may sponge to different miRNA and mRNA thus modulating the expression of numerous oncogenic or tumor-suppressive genes. Proteins such as c-MYC and HIF1α are frequently stabilized and/or upregulated whereas, in the same way, lncR-NAs alter signaling pathways favoring cancer progression. For instance, mTOR/STAT3 is commonly dysregulated in various cancers.
In conclusion, this review highlights lncRNAs as crucial regulators of cancer glucose metabolism. A blockade of these mechanisms may alleviate cancer progression, therefore rendering lncRNAs a promising therapeutic target.