Insights into the Regulatory Role of Non-coding RNAs in Cancer Metabolism

Abstract

Cancer represents a complex disease originated from alterations in several genes leading to disturbances in important signaling pathways in tumor biology, favoring heterogeneity that promotes adaptability and pharmacological resistance of tumor cells. Metabolic reprogramming has emerged as an important hallmark of cancer characterized by the presence of aerobic glycolysis, increased glutaminolysis and fatty acid biosynthesis, as well as an altered mitochondrial energy production. The metabolic switches that support energetic requirements of cancer cells are closely related to either activation of oncogenes or down-modulation of tumor-suppressor genes, finally leading to dysregulation of cell proliferation, metastasis and drug resistance signals. Non-coding RNAs (ncRNAs) have emerged as one important kind of molecules that can regulate altered genes contributing, to the establishment of metabolic reprogramming. Moreover, diverse metabolic signals can regulate ncRNA expression and activity at genetic, transcriptional, or epigenetic levels. The regulatory landscape of ncRNAs may provide a new approach for understanding and treatment of different types of malignancies. In this review we discuss the regulatory role exerted by ncRNAs on metabolic enzymes and pathways involved in glucose, lipid, and amino acid metabolism. We also review how metabolic stress conditions and tumoral microenvironment influence ncRNA expression and activity. Furthermore, we comment on the therapeutic potential of metabolism-related ncRNAs in cancer.

Keywords: cancer metabolism; metabolic reprogramming; miRNAs; ncRNA regulation.

Figure 1

Biological and mechanical overview of non-coding RNAs. (1, 2) Biogenesis of microRNAs and their main mechanisms of action. The pri-miRNA is transcribed by pol II polymerase and digested by the RNase DROSHA originating a pre-miRNA (70 nt), which is exported to the cytoplasm by exportin 5. Then, another RNase, Dicer, digests the pre-miRNA to generate a mature duplex miRNA (~22 nt). One strand of this duplex is then incorporated in the miRISC complex (Ago2-microRNA) to target mRNA by perfect complementarity producing transcript degradation (1) or an imperfect one promoting translation repression (2). Conversely, (right side), general functions of lncRNAs are described. (3) Recruitment of transcription factors to promote transcription of target genes or (4) recruitment of chromatin modifiers and thus (6) promoting remodeling of the chromatin architecture. Other functions of lncRNAs are (5) control of alternative splicing of mRNA, and (7) control of translation rates favoring or inhibiting polysome loading to mRNAs, (8) acting as a decoy to preclude access of regulatory proteins to DNA. (9) The interaction between microRNAs and endogenous competent RNAs (ceRNAs) is a redundant system to regulate mRNA expression by lncRNAs-microRNAs; this mechanism is known as sponge function by lncRNAs. Thus, microRNA sequestration by lncRNA prevents microRNA functions on its target.

Figure 2

Overview of glycolysis, OXPHO, and lipid metabolism. (A) This figure describes the connections between metabolic sub-products that take part in different metabolic process, as well as enzymes and substrates that maintain the normal metabolic environment. Glycolysis occurs in the cytosol when D-glucose is internalized into the cell through the membrane transporters GLUT1, 2, 3, and 4. Through a system of coupled enzymatic reactions, D-glucose is converted into pyruvate, which enters into the TCA cycle, and OXPHO. When the amount of oxygen is limited, pyruvate is converted into lactate. Conversely, in the mitochondria, the TCA cycle is coupled to OXPHO which represents the largest source of metabolic energy. Pyruvate is oxidized and converted into acetyl coenzyme A, which enters the TCA cycle that generates reducing molecules (NADH and FADH₂) to produce ATP by oxidative phosphorylation. Finally, fatty acids can be converted into acetyl coenzyme A by ß-oxidation to then generate energy through the TCA cycle and OXPHO (B). Glycolysis regulation by miRNAs and lncRNAs under oncogenic conditions. Expression of the GLUT transporter family is regulated by ncRNAs, thus altering the internalization rate of glucose. Other molecules are under ncRNAs regulation pathways, such as hexokinase-2 enzyme, which mediates the transformation of glucose to glucose 6-phosphate, PKM2 enzyme involved in pyruvate synthesis, LDHB and LDHA enzymes that convert pyruvate into lactate, and PDHK, responsible for the synthesis of Acetyl coenzyme A from pyruvate.

Figure 3

Landscape of lipid and amino acid metabolism regulated by ncRNAs in tumors. Micro and lncRNAs can regulate the metabolism of amino acids through the regulation of enzymes related with these metabolic pathways, favoring the disposition of amino acids as important sources of energy. There is also a fine regulatory loop between microRNAs and lncRNAs than can actively impact metabolic networks.

Figure 4

Overview of ncRNA regulatory network over OXPHO in cancer. In this picture we show how ncRNAs are involved in the regulation of OXPHOS, generation of ROS, or mediating alternative splicing of mitochondrial enzymes.

Figure 5

ncRNAs as novel therapeutic strategies in cancer metabolism. Targeting cancer metabolism represents a novel resource to develop anti-cancer therapies. Now a days, there are different techniques developed to specifically modulate metabolic pathways, some of them are dedicated to silencing (LNA) or re-expressing (miRNA mimic) ncRNA transcripts (Phan et al., 2014). These systems can be delivered by intratumoral, intraperitoneal, and intravenous injections, through systemic adenovirus-associated virus (AAV), or in complexes with neutral lipid emulsions (Drakaki et al., 2013). In addition to these technologies, cholesterol-modified miRNAs (chol-anti-miRs) exhibit improved pharmacokinetics and antitumor efficacy. Human (1) The development of hepatocellular carcinoma (HCC) in persons who are persistently infected with hepatitis C virus (HCV) is a growing problem. A phase II trial of the LNA anti-miR-122 is being carried out for treatment of HCV infection (Lindow and Kauppinen, 2012). Xenograft mouse models (2) chol-anti-miR-221 effectively suppresses liver tumor growth (Park et al., 2011). (3) Systemic administration of miR-124 suppresses liver cancer growth through suppression of the IL6/STAT3 inflammatory pathway (Hatziapostolou et al., 2011). (4) AAV delivery of miR-26a or miR-122 suppresses MYC-driven liver carcinogenesis without affecting normal hepatocytes (Kota et al., ; Hsu et al., 2012). (5) Neutral lipid emulsions (NLE) to deliver let-7 which targets RAS and MYC oncogenes, as well as miR-34, reduces tumor size in lung cancer (Trang et al., 2011). (6) miR-101 and miR-376b are miRNAs, which negatively regulate the autophagy pathway (Frankel et al., ; Korkmaz et al., 2012). Furthermore, overexpression of miR-101 suppressed tumor development and efficiently reduced tumor size in liver cancer (Su et al., 2009). (7) Over-expression of miR-101 can effectively reduce tamoxifen-induced autophagy and enhance the sensitivity of breast cancer cells to tamoxifen treatment (Frankel et al., 2011). (8) Recombinant lentivirus administration of miR-30a (inhibitor of autophagy by down-modulating BECN1), can enhance sensitivity to imatinib cytotoxicity in chronic myeloid leukemia, increasing tumor cell apoptosis (Yu et al., 2012). In vitro (cell line models). (9) Up-regulation of miR-125a in cervical cancer (CC) models sensitized to paclitaxel by down-regulating STAT3 (Fan et al., 2016). (10) Re-expression of miR-30a can sensitize tumor cells to cisplatin via mediating autophagy in HeLa, MCF-7 and HepG2 (Zou et al., 2012). (11) Over-expression of miR-101 sensitized human lung carcinoma cells to radiation treatment (Yan et al., 2010).