The roles and molecular mechanisms of non-coding RNA in cancer metabolic reprogramming

Cancer is one of the most common fatal diseases, which seriously threatens human lives and health. According to the most recent data in 2023, about two million new cancer cases and almost sixty thousand cancer deaths are projected to occur in the United States [1]. Thus, it is urgent to find new biomarkers and therapeutic strategies for cancer with great significance.

Currently, energy metabolic reprogramming, one of the Hallmarks of cancer, has become the hot spot in the research field [2]. In 1921, German scientists discovered the “Warburg effect”, also known as “aerobic glycolysis”, which meant that apart from normal cellular oxidative phosphorylation, cancer cells undergo aerobic glycolysis under aerobic conditions by taking in massive glucose to provide numerous Adenosine triphosphate (ATP) and biosynthetic materials for rapid proliferation. It is a huge breakthrough in the field of cancer metabolism research. Besides glucose metabolism reprogramming, cancer cells can also induce the alterations of lipids and amino acids et al. to meet the requirements for malignant progress. The altered energy metabolism of cancer cells can reshape the cancer microenvironment, which facilitates the maintenance of malignant phenotype and immune escape [3, 4]. Importantly, targeting specific metabolic pathways of cancer cells or simultaneously synergizing other therapeutic strategies is one of the effective means to improve the efficacy of cancer therapy [5, 6].

Non-coding RNAs (ncRNAs) are novel gene regulatory molecules, mainly including miRNAs, long non-coding RNAs (lncRNAs) and circular non-coding RNA (circRNAs) et al. In recent years available evidence is increasingly indicating that dysregulated ncRNAs play a significant role in the progression of cancer malignancy through metabolic reprogramming [7, 8]. Consequently, there is a pressing need to elucidate the potential regulatory mechanisms of ncRNAs in the cancer metabolic network for the development of carcinogenesis, as this knowledge holds great promise for future prevention and treatment strategies. This review aims to provide an updated overview of the latest research progress on the molecular mechanisms of ncRNAs in cancer energy metabolic reprogramming.

It is known that energy metabolism undergoes great changes during the development of cancer, referring to the “Warburg effect”, the production of vast amounts of ATP and lactate by aerobic glycolysis of cancer cells under aerobic conditions through massive glucose uptake to support the acquisition and maintenance the malignant phenotype [9]. The initiation of aerobic glycolysis is facilitated by the glucose transporter1 (GLUT1) mediated abnormal transportation of glucose and the abnormal expression of enzymes involved in glycolysis. This phenomenon is induced by oncogenes like c-Myc and HIF-1α, whereas cancer suppressors such as p53 and OVOL2 exhibit an opposing effect. The activation of aerobic glycolysis results in the provision of substantial resources for cancer cells, encompassing ATP and metabolic intermediates derived [10‐15]. In addition to facilitating the malignant phenotype of cancer cells, lactate, a byproduct of aerobic glycolysis in cancer cells, can be extracellularly transported through monocarboxylate transporter protein 4. This transport mechanism contributes to the creation of an acidic microenvironment within cancer cells, ultimately leading to the polarization of M2 macrophages and the promotion of immunosuppressive function in Treg cells [3]; Conversely, it inhibits the activation of cytotoxic T cells and depletes the interferon-γ (IFN-γ) secretion function of natural killer (NK) cells [3, 16, 17]. Furthermore, increased lactate abundance in the tumor microenvironment (TME) also promotes cancer immune escape through epigenetics [18]. In conclusion, glucose metabolic reprogramming promotes the malignant progression of cancer cells and its targeting can be a promising strategy to suppress cancer progression.

The mechanisms of lipids including absorption, synthesis, and oxidation in cancer cells primarily distinct from normal cells [19]. These processes are extensively regulated by transcription factors such as peroxisome proliferator-activated receptors and sterol regulatory progenitor proteins [20, 21]. Cancer cells require a large amount of lipids and cholesterol to meet their raised demand by increasing the uptake of exogenous lipids, and lipoproteins and activating the expression of enzymes related to the de novo synthesis of lipids and cholesterol. The increased expression of fatty acids in vivo can modify proteins at the epistatic level. An emerging study shows that palmitoylation modification of GLUT1 regulates its plasma membrane localization impairing glycolysis and cell proliferation in cancer cells [22]. Furthermore, ferroptosis is driven by the peroxidation of polyunsaturated fatty acids catalyzed by ferrous ions [23]. Changes in lipid metabolism in cancer cells promote aberrant accumulation of lipids in TME, which in turn promotes unusual accumulation of lipids in cancer-infiltrating immune cells leading to the translation between immunosuppressive and anti-inflammatory phenotype [5, 24‐26]. Intriguingly, the abnormal accumulation of cholesterol in cancer cells can contribute to the stable expression of programmed death ligand-1 (PD-L1) by binding to cholesterol-recognition amino acid consensus motifs on PD-L1, resulting in the development of cancer immune escape [5]. As its low response to immunotherapy, targeting lipid metabolism in cancer may be a significant approach to improve the efficiency of immune therapy and inhibit cancer progression.

The metabolic reprogramming of amino acids plays an essential role in the development of cancer. In addition, amino acids affect the function of immune cells in anti-cancer immunity [27]. Accumulated evidence shows that most cancer cells strongly depend on glutamine known as “glutamine addiction” as it stagnates in growth and even dies once cancer cells are deprived of glutamine [28]. Cancer cells reduce the activation and infiltration of CD8⁺ T cells and recruit myeloid-derived suppressor cells (MDSCs) by increasing the secretion of granulocyte colony-stimulating factor through the massive consumption of glutamine in TME [3]. However, restricting glutamine uptake by cancer cells increases PD-L1 expression through stimulation of Ca2⁺/NF-κB signaling, resulting in diminished anticancer activity of T cells, which may be successfully eliminated by anti-PD-L1 therapy [6]. The altered metabolism of serine, tryptophan and glycine in cancer cells has likewise received considerable attention. The classically activated macrophages (M1) polarization of macrophages induced by IFN-γ can be significantly enhanced by inhibiting the ab initio synthesis of serine or by limiting the uptake of exogenous serine [29]. Serine is the main substrate of one-carbon units for nucleotide synthesis in vivo, however, in cancer cells with high expression of indoleamine 2, 3-dioxygenase 1(IDO1), tryptophan could replace serine as the main substrate of one-carbon units [30]. High levels of IDO and tryptophan 2,3-dioxygenase (TDO) in cancer inhibit the cancer-killing effects of T cells by reducing tryptophan levels in TME [31]. Related studies have proved that immunotherapy induces IFN-γ increasing release by activation of CD8⁺ T cells, downregulates the expression of the xc-subunit of the glutamate-cystine reverse transport system and weakens the uptake of cystine by cancer cells, thereby promoting cancer cell death [32]. Therefore, it may have the potential to inhibit the malignant progression of cancer cells as well as improve the efficacy of anticancer therapy by targeting specific amino acid metabolic pathways.

In addition, aberrant activation of oncogenes can promote anabolism through multiple signaling pathways, such as PI3K/Akt/mTOR, HIF-1α and sterol-regulatory element binding proteins (SREBP) et al. [33]. TME provides the fundamental materials for cancer growth, and cancer metabolic reprogramming changes the level of substances in TME, indirectly affecting the release of inflammatory factors and anti-cancer function of immune cells in TME [34]. In conclusion, as metabolic reprogramming of cancer cells facilitates the development of metabolic phenotype for malignant progression. it may be a potential strategy to effectively suppress their malignant progression by changing the metabolic phenotype of cancer.

For decades, ncRNAs, used to be regarded as by-products of transcription, have been found to play essential roles in a variety of important cellular life activities, which include chromatin remodeling, transcription, post-transcriptional modifications (PTMs) and signal transduction [35‐39]. NcRNAs refer to a class of RNAs that have no protein-coding functions in cells, including ribosomal RNA (rRNA), transfer RNA (tRNA), small nuclear RNA (snRNA), and small nucleolar RNA (snoRNA), piRNA (PIWI-interacting RNA), microRNA (miRNA), lncRNAs, and circ RNAs [40, 41]. In this review, we mainly focus on microRNAs, lncRNAs and circ RNAs.

MicroRNAs are a set of ncRNAs with 20nt nucleotide and play a key regulatory role at the post-transcriptional level of messenger RNA (mRNA) by binding to the 3’-untranslated regions (3’-UTR) of the target gene to degrade the mRNA of the target gene or inhibit the translation process of the target gene [42, 43]. LncRNAs are a class of special RNA molecules that are longer than 200 nucleotides and without protein-coding potential, and their biological generation is similar to mRNAs [44]. However, due to the splicing efficiency of lncRNAs being lower than mRNAs, most lncRNAs are retained in the nucleus after transcription involved in mediating interactions between DNA and proteins, adsorbing microRNAs, and binding to proteins as decoys, which contribute to regulating chromatin structure, remodeling chromatin and chromatin modification. And only a small fraction is exported to the cytoplasm [45‐47]. CircRNAs are novel ring-like molecules formed by reverse shearing of exons. The 3’ and 5’ ends of circ RNA are linked to form a covalently closed loop structure, which confers a longer half-life, more stability and less sensitivity to RNA exonucleases. Similar to lncRNAs, circRNAs have played an important regulatory role in gene expression at epigenetic, transcriptional or post-transcriptional levels [48‐50]. There is sufficient evidence showing that ncRNAs are key regulators of metabolic reprogramming, which results in cancer rapid development [51‐53]. Importantly, some ncRNAs serve as metabolic-related oncogenes, while some other ncRNAs act as metabolic-related suppressors. Thus, it is urgent to figure out the potential molecule mechanism of dysregulated metabolism mediated by ncRNAs in carcinogenesis, which may be a promising strategy for therapy in the future.

Numerous research has demonstrated that dysregulated ncRNAs related to metabolic networks can promote or suppress carcinogenesis, by facilitating cancer to acquire and maintain aggressive malignant phenotype and to target multiple metabolic signaling pathways [54‐62]. Therefore, we update the latest research progress on the mechanisms of ncRNAs in metabolic reprogramming from three perspectives: glucose, lipid and amino acids, respectively.

Chemotherapy, radiation, targeted therapy and immunotherapy are the major strategies used for malignant cancers. However, the outcome of patients does not remain satisfactory due to limitations such as multi-drug resistance and tumor relapse [156]. Numerous types of research have implicated that ncRNAs may be a potential target to overcome therapeutic tolerance. Nevertheless, the potential regulatory mechanism for the occurrence of therapeutic tolerance and metabolic reprogramming in cancer needs to be further investigated.

There are numerous studies have demonstrated that ncRNAs are involved in multiple metabolic pathways or signaling pathways to regulate the genesis and progression of cancer cells [174‐176]. Therefore, ncRNAs-based metabolic reprogramming may provide promising prospects in overcoming cancer therapeutic tolerance and improving related anti-cancer drugs’ therapeutic efficiency. Elucidating the interaction and possible mechanism between ncRNAs and metabolic reprogramming has shed some insights into understanding the pathogenesis and provided a theoretical foundation for cancer research.

The treatments suppressing cancer progression through the metabolic networks mediated ncRNAs have been summarized in Fig. 7. Ni et al. revealed that simvastatin could decrease lncRNA SNHG29 expression and, thereby inhibit activation-induced PD-L1 expression, which enhances anti-cancer immunity [124]. Therefore, the use of cholesterol scavengers may significantly enhance the efficacy of immunotherapy [5]. Besides, numerous drugs affect ncRNA-mediated glucose reprogramming to suppress cancer progression. Wu et al. revealed that kaempferol reduced PKM2 expression and thereby inhibited cancer progression by upregulating miR-339-5p [177]. LncRNA UCA1 is documented to contribute to paclitaxel resistance and promote glycolysis by facilitating the expression of HK2 and LDHA [178]. LncRNA FGD5-AS1 promotes glycolysis and 5-FU resistance of CRC cells by acting as a ceRNA for miR-330-3p and upregulating HK2 in CRC. While erlotinib could effectively re-sensitivity CRC to 5-Fu by targeting lncRNA FGD5-AS1 [179].

Importantly, targeting dysregulated ncRNAs by delivering small molecule drugs to the body provides a novel approach for future cancer therapy. Antisense oligonucleotides (ASO) of lncRNA AGPG delivered to patients with ESCC have been demonstrated to effectively limit glycolysis and cell proliferation to inhibit the expression of PFKFB3 [180]. Song et al. demonstrated that siRNA specific to lncRNA HISLA inhibits glycolysis and chemoresistance in breast cancer by mediating the interaction of HIF-1α with prolyl hydroxylase 2 (PHD2) [181]. The study by Yun et al. has identified that applicate inhibition of LINRIS via in vivo-optimized RNA interference (RNAi) and oxaliplatin could effectively suppress glycolysis and cell proliferation in CRC [46]. The reprogramming of energy metabolism mediated by ncRNAs is a potential target for some drugs [124, 177‐179]. As a novel therapeutic approach, the combination of small molecule inhibitors with cancer therapy can significantly suppress the progression of cancer [180, 181]. However, the main challenge of their application currently lies in how to precisely target specific cell types. More notably, despite the rapid development of CAR-T cell therapy in non-solid cancers, its treatment currently faces many challenges [182]. Whether lncRNAs can serve as ideal targets to provide new strategies to improve the efficiency of CAR-T cell immune treatment deserves further investigation.

Energy metabolic reprogramming is a fundamental feature of cancers. Cancer cells reprogram substances such as glucose, lipid and amino acids to satisfy their needs for rapid proliferation and adaptation to external stress, which is driven by dysregulated ncRNAs. Interestingly, numerous studies have suggested that ncRNAs derived from gut microbial and viruses are involved in metabolic reprogramming which may be an emerging direction for future research. Importantly, sufficient studies have demonstrated that alterations in metabolic pathways mediated by ncRNAs are closely associated with the development of cancer treatment tolerance, therefore, the targeted ncRNAs therapy in combination with conventional cancer therapy may be an effective strategy to overcome low response or tolerance of cancer therapy. However, current studies on the metabolism of ncRNAs are mainly focused on glucose and lipids, whereas molecular mechanisms in amino acid metabolism and more systematic research are still required. Moreover, the issues about how to target ncRNAs in specific cells to improve the efficacy of treatment need to be further researched. In conclusion, this study emphasizes the feasibility of targeting lncRNAs and presents new insights into the molecular signaling pathways associated with metabolism.