Current Gene Therapy, 2012, 12, 285-291
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MicroRNAs and the Warburg Effect: New Players in an Old Arena Ping Gao1,2,*, Linchong Sun1, Xiaoping He1, Yang Cao1 and Huafeng Zhang1 1
School of Life Science, University of Science and Technology of China, Hefei, China, 230027; 2Division of Hematology, Department of Medicine, the Johns Hopkins University School of Medicine, Baltimore, MD, 21205 USA Abstract: It is known that tumor cells adapt characteristic metabolic phenotypes during cancer initiation and progression. The hallmark of tumor metabolism is aerobic glycolysis, or Warburg Effect, which was first described more than 80 years ago. Unlike normal cells, most cancer cells produce energy by a high rate of glycolic catabolism to lactate in the cytosol, rather than by oxidation of pyruvate in mitochondria, even in the presence of oxygen. Progress over the past decade has revealed that alterations of oncogenes and tumor suppressors are responsible for such metabolic reprogramming in cancer cells, however, the underlying molecular basis remains largely unknown. Mounting evidence shows the interplay between microRNAs and oncogenes/tumor suppressors, via key metabolic enzyme effecters, which could facilitate the Warburg Effect in cancer cells. In this review, we will summarize our current understanding of the roles of microRNAs, in particular their interplay with oncogenes/tumor suppressors such as cMyc, HIF-1 and P53, in tumor metabolism.
Keywords: cMyc, HIF-1, miRNA, P53, tumor metabolism, Warburg effect. AN OLD ARENA: WARBURG EFFECT In 1857, Louis Pasteur described that aerating yeast broth caused yeast cell growth to increase, while conversely, fermentation rate decreased. For over a century, this phenomenon of increased conversion of glucose to lactate in hypoxic cells has been regarded as a critical cellular metabolic adaptation to hypoxia in normal cells. In contrast, Otto Warburg observed that most cancer cells predominantly produce energy by a high rate of glycolysis followed by lactate fermentation in the cytosol, rather than by oxidation of pyruvate in mitochondria like most normal cells [1]. Warburg described that cancer cells typically have glycolytic rates that are up to 200 times higher than those of their normal counterparts even in the presence of abundant oxygen and he postulated that this change in metabolism is the fundamental cause of cancer. He proposed that a defect in mitochondria was responsible for the aerobic glycolysis observed, which is now referred to as the Warburg effect [2]. Today it is known that alterations in oncogenes and tumor suppressor genes are responsible for malignant transformation of normal cells [3, 4]. Several of these mutations are responsible for the Warburg Effect in cancer cells [5], however, the fundamental pathways by which these alterations give rise to the Warburg Effect and subsequent cancer development are still largely unknown. NEW PLAYERS: miRNAs Since the discovery of lin-4 and let-7 in C. elegans almost a decade ago [6-8], more than 1000 microRNAs (miRNAs) have been identified. miRNAs are small non-coding regulatory RNAs of 17-24 nucleotides which regulate target gene expression at post-transcriptional level. The genes *Address correspondence to this author at the School of Life Science, University of Science and Technology of China, Hefei, China; 230027, Tel: 86551-360-7033; E-mail:
[email protected]
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encoding miRNAs are transcribed to a primary RNA which has a hairpin stem-loop structure, cleaved by Drosha and DGCR8 and turn into a short precursor miRNA, or premiRNA, which is transported into the cytoplasma by exportin-5 and processed into mature miRNA through the RNase III enzyme, Dicer. When the sequence of certain miRNA is perfectly complementary to the seed sequence primarily at 3’UTR of the target mRNA, the target mRNA will be degraded. However, if there is only partial complementarity, the miRNAs will disturb the translation of target mRNA into proteins without causing mRNA degradation [9, 10]. A specific miRNA is often known to have multiple targets and one gene may be regulated by multiple miRNAs. Several miRNAs have been documented to play important roles in physiological processes such as the cell cycle, mitochondrial biogenesis, apoptosis and pathological conditions, such as tumorigenesis and metastasis [11-13]. AnokyeDanso et al. reported that miR-302, a miRNA cluster regulated by sox2 and oct4, can replace Yamanaka factors (Myc, Oct4, Sox2 and KLF4) to directly reprogram human somatic cells (fibroblasts) into induced pluripotent stem cells (iPSCs) [14]. In mouse models of hepatocellular carcinoma, Kota et al. described that expression of miR-26a using adenoassociated virus resulted in dramatic tumor suppression [15]. These are only a few examples of the roles that miRNAs can play. We are just beginning to appreciate the potency and complexity of the miRNA regulatory network in physiological and diseased conditions. In this review, we will focus on the emerging roles of miRNAs in cancer metabolism. NEW GAMES: INTERPLAY OF miRNAS AND ONCOGENES/TUMOR SUPPRESSORS IN WARBURG EFFECT It has been established that aberrant expression of oncogenes and tumor suppressors is responsible for normal cell © 2012 Bentham Science Publishers
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transformation to malignant cells. However, the pathways by which these alterations lead to tumor development are largely unknown. Oncogenes and tumor suppressors may regulate a number of metabolic enzymes and their aberrant expression may provide a growth advantage to cancer cells [5]. Oncogenes such as cMyc and HIF-1 have been documented to regulate almost all of the glycolytic enzymes [16], rendering metabolic shift to glycolysis in cancer cells, even under normoxic condition. Tumor suppressor P53 is also known to regulate diverse metabolic effecters such as TIGAR, which is a key enzyme in glycolytic pathways [17], and SCO2 which is a mitochondrial respiratory chain component [18]. It is intriguing that recent advances suggest that the roles of oncogenes/tumor suppressors are more complicated than previously anticipated; the emerging interplay between miRNAs and oncogenes/tumor suppressors has added yet another layer of complexity to the regulatory network of metabolic pathway in cancer cells [19]. cMyc and miRNAs The cMyc proto-oncogene was discovered more than three decades ago as the cellular homolog of the retroviral vMyc gene that is sufficient to cause a variety of chicken tumors [20]. cMyc belongs to the Myc family of genes including N-Myc and L-Myc and is a transcription factor and master regulator that integrates cell proliferation with cell metabolism. Many studies have identified that cMyc is frequently altered in human cancers. Aberrant expression of the cMyc oncogene was observed in about 30% of human cancers, including many commonly occurring cancers, such as prostate, colon and breast carcinomas [21, 22]. Numerous genes have been identified as direct and indirect cMyc targets, thanks to high throughput approaches such as gene expression microarray studies and chromatin immunoprecipitation which maps direct cMyc genomic binding sites [23]. Several studies have revealed important roles of cMyc in regulating miRNAs. O’Donnell et al. were the first to demonstrate that cMyc directly upregulates a pro-tumorigenic group of miRNAs known as the miR-17-92 cluster [24]. Through the analysis of human and mouse models of B cell lymphoma, Chang et al., further identified that cMyc regulates a much broader set of miRNAs than previously anticipated and the predominant consequence of activation of cMyc is widespread repression of miRNA expression [25]. Lin et al. documented a role of cMyc in the maintenance of stem cell pluripotency through the regulation of a set of miRNAs that are implicated in differentiation as well as selfrenewal [26]. More recently, investigators have established connection between miRNAs and cMyc-regulated metabolic changes in cancer cells [27]. The discovery that cMyc up-regulated LDHA in cancer cells provided a great foundation for cancer metabolic studies [28]. cMyc is now known to transcriptionally regulate the majority of the enzymes involved in glycolysis pathways [29]. New evidence is emerging to demonstrate that glycolysis is also controlled by miRNAs. Zhu et al. recently reported that Lin28/let-7 axis regulates glucose metabolism in mouse models [30]. The let-7 tumor suppressor miRNAs are known to regulate oncogenes including cMyc, while the RNA-binding proteins Lin28a/b, which are cMyc targets, promote malignancy by inhibiting let-7 biogenesis. When
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overexpressed in mice, both Lin28a and Lin28b promote an insulin-sensitized state that resists high-fat-diet induced diabetes via the PI3K-mTOR pathway. Muscle-specific loss of Lin28a or overexpression of let-7 results in insulin resistance and impaired glucose tolerance. These results establish the Lin28/let-7 axis as a central regulator of mammalian glucose metabolism. Given the “Sweet tooth” nature, or enhanced glycolysis, of cancer cells and the well established regulatory relationship between cMyc and Lin28/let-7, it is highly conceivable that Lin28/let-7-cMyc axis may play central role in regulating aerobic glycolysis, or Warburg effect, in cancer cells. However, this hypothesis is yet to be tested experimentally. Besides switching to aerobic glycolysis, cancer cells are known to avidly use glutamine as energy and biosynthesis sources, a process also regulated by cMyc and miRNAs. In this regard, Gao et al. discovered that cMyc suppression of miR-23a/b enhances mitochondrial glutaminase (GLS) expression and glutamine metabolism [27]. Through proteomic analysis of mitochondria from high cMyc-expressing human B lymphocytes, they identified GLS, among other mitochondrial proteins, as a cMyc target with more than 10-fold induction in protein levels. Further analysis revealed that unlike glutamine transporters ASCT2 and SLC7A25, which are direct cMyc target genes that are transcriptionally regulated, GLS protein level was induced by cMyc through direct suppression of miR-23a and miR-23b. Importantly, the suppression of GLS expression under low-cMyc condition in P493 lymphoma and PC3 prostate cancer cell was rescued by treatment with antisense miR-23a and miR-23b LNAs, indicating that the real mediators of cMyc regulation of GLS protein expression are miR-23a and miR-23b. Since GLS is essential for cMyc-mediated cell proliferation and its expression is frequently increased in human cancers, the unique means by which cMyc regulates GLS via suppression of miR-23a/b uncovers a previously unsuspected link between oncogenes and miRNAs in modulating cancer metabolism and progression [27]. More recent reports demonstrated that enhanced utilization of glutamine by cancer cells facilitates glucose-independent TCA cycle under hypoxia conditions [31]. Metallo et al. described that reductive glutamine metabolism mediates lipogenesis under hypoxia, underlining that cancer cells excessively use glutamine not only as energy sources but also for biosynthesis [32]. By-product of glutamine catabolism, NH3, is reported to stimulate autophagy to protect cells under stressed conditions [33]. Those examples illustrate the significance of miRNA-dependent cMyc regulation of glutamine metabolism in cancer cell survival and tumor development, usually under hypoxic microenvironments. HIF-1 and miRNAs Hypoxia-Inducible Factor-1 (HIF-1), a master regulator of oxygen homeostasis among all metazoan species, is a heterodimer composed of hypoxia-inducible subunit—HIF-1 and a constitutive subunit—HIF-1. Both of the subunits belong to basic helix–loop–helix family of transcription factors [34]. Hypoxia is a hallmark of the tumor microenvironment and as a result, the role of HIF-1 in cancer development has been intensively studied. Like cMyc, HIF-1 has been documented to regulate glucose transporters (Glut1, Glut3)
MicroRNAs and the Warburg Effect: New Players in an Old Arena
and many glycolytic enzymes (HK1, HK2, GPI, ALDA and LDHA). It has been reported that HIF-1, via activation of its target gene PDK1, shut off the entry of pyruvate into TCA cycle, switching to glycolytic metabolism, or Warburg Effect, in cancer cells [35]. Recent data suggests that hypoxiarelated miRNAs are involved in tumor progression and tumor metabolism. miRNAs regulated by hypoxia such as miR-210 have been demonstrated to participate in the tumor progression [36]. miR-21 can stimulate angiogenesis by inducing HIF-1 expression [37], miR-20b and miR-22 limits HIF-1 expression in breast cancer cells and colon cancer cells [38, 39], whereas miR-424, unique to the endothelial cell, induced by hypoxia can enhance HIF-1 activity in a novel way [40]. Mitochondrial functions of tumor cells are known to be dysregulated because of unbalanced metabolism. Indeed, we have found that HIF-1 can suppress cMyc, thus leading to reduction of PGC-1, a transcriptional regulator of oxidative energy metabolism, and inhibited mitochondrial biogenesis in VHL-deficient renal cell carcinoma [41]. Recently, Eichner et al. have found that miR-378*, located in the first intron of PPARGC1b (PGC-1), is regulated by ERBB2. During breast cancer progression, elevated miR-378* can target important metabolism regulators, ERR and GABPA, two PGC-1 partners, then bring about the metabolic shift from TCA to Warburg Effect [42] These results indicate that the regulation network of Warburg Effect is more intricacy than imaged. Fig. (1). Huang et al. reported that miR-210, a miRNA directly induced by HIF-1 in a variety of tumor types, can inhibit tumor initiation. They attributed this activity to cell cycle arrest by antagonizing cMyc transcriptional activity [36, 43], however, this is not in accordance with reports from other groups. More recently, it has been documented that HIF-1induced miR-210 facilitates tumor cell survival via modula-
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tion of mitochondrial function under hypoxic stress [44]. ISCU has been identified as a miR-210 target that controls ROS production in mitochondria. When ISCU is downregulated, Fe-S proteins, which are important components in the active site of enzymes involved in TCA cycle, will decrease, resulting in repression of mitochondrial respiration [45]. In hypoxia, repression of electron transport balances the reduced oxygen tension and increases ATP levels via enhanced glycolysis [46]. HIF-1 can also be activated under normoxic conditions by oncogenic signaling pathways, including PI3K [47]. MiR-210 induced by HIF-1 is also shown to play a role in the regulation of cell cycle and can be a prognostic marker in breast cancer [48, 49]. Thus, miR210 induced by HIF-1 integrates cell proliferation with cell metabolism during cancer progression. miRNAs also contribute to HIF-1 modulation via metabolic enzymes. In renal carcinomas, Phang et al. described that miR-23b*, the less predominant form of the expressed precursor of the miR-23b, regulates tumor suppressor POX/PRODH, proline oxidase/proline dehydrogenase, which is a mitochondrial inner-membrane enzyme catalyzing the transfer of electrons from proline, producing P5C[50]. Interestingly, miR-23b* mimics not only decreased the induction of POX/PRODH but also modulated the decrease in HIF-1, a recapitulation of the effect of POX/PRODH on levels of HIF-1 reported earlier [50]. This was especially relevant because the HIF-1 signaling system plays a special role in renal carcinogenesis, highlighting the intriguing interplay between miRNAs and HIF-1 in facilitating metabolic switch and carcinogenesis. P53 and miRNAs P53 is the most highly mutated tumor suppressor discovered in many types of human malignancies. Loss of function mutation of P53 gene has been documented in more than
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Fig. (1). Metabolic shift (Warburg Effect) by oncogene and microRNAs via PGC-1 pathways. (A) Warburg Effect induced by HIF-1/PGC1 pathway as depicted in reference [41] (B) Warburg Effect induced by PGC-1/ERR pathway as depicted in reference [42] (Abbreviations: PGC-1: peroxisome proliferative activated receptor, gamma, coactivator 1 beta; ERBB2: v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 neuro/glioblastoma derived oncogene homolog (avian); ESRRA: estrogen-related receptor alpha; ESRRG (ERR): estrogenrelated receptor gamma; TFs: transcription factors ; GABPA: GA repeat binding protein alpha).
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50% of human cancers and the pathways by which P53 defect leads to tumor development have been well established in the past two decades. As a genome guardian, P53 regulates cell cycle checkpoint, stress response, DNA repair and somatic mutation, thereby controlling cell death or cell cycle entry [51, 52]. Recently, P53 has been reported to affect cellular metabolism or respiration by regulating key enzymes in glycolysis pathway, respiratory chain and PPP pathways [16, 17, 53]. Progress in this field is shifting the paradigm towards a more complicated network controlled not only by transcriptional mechanism but also by non-coding RNAs. The connections and interplay between P53 and non-coding RNAs, including miRNA [54], lincRNA [55, 56] and ceRNA [57], in cancer biology are at the forefront of the P53 research. A recent study showed a miRNA linking P53 and HIF-1 in controlling glucose usage, cell proliferation and tumor growth under hypoxic microenvironment [58]. Yamakuchi et al. discovered miR-107 as a P53 target [58]. Interestingly, P53 directly regulated miR-107 via its 5’UTR, resulting in degradation of HIF-1 without affecting HIF-1. P53 induced miR-107 expression and decreased hypoxic signaling resulting in decreased glucose uptake and tumor growth due to lower HIF-1 activity [58]. This evidence demonstrates that tumor growth is not only driven by tumor microenvironment but also by mutations of host genes intertwined with miRNA expression. Along this line, Shin et al. reported that, several miRNAs, including miR-210, miR-500 and miR-516-5p, were up-regulated in the irradiated P53-null HCT116 cells [59]. The up-regulation of miR-210 is particularly interesting since miR-210, also known as being up-regulated by HIF-1, has been reported to regulate cellular respiration of mammalian cells via ISCU1/2 [45]. As a consequence, P53 mutation might render cancer cells a more glycolytic metabolism phenotype via a potential P53-miR210-ISCU1/2 pathway. P53 is also reported to regulate cMyc via miRNAs. Sachdeva et al. described that a putative tumor suppressor, miR-145, is expressed through the phosphoinositide 3-kinase (PI3K)/Akt and P53 pathways [60]. They reported that P53 transcriptionally induces the expression of miR-145 by interacting with a potential P53 response element (P53RE) in the miR145 promoter. They further showed that cMyc is a direct target for miR-145. Hence, the intertwining of miRNAs and oncogenes/tumor suppressors is becoming very complicated. What’s more perplexing is that, instead of being a consistent tumor suppressor, P53 can also support melanoma cell survival by up-regulation of miR-149* under ER stress [61]. Moreover, reports also indicated that P53 is regulated by miRNAs [46]. Park et al. reported that miR-29 family members, miR-29a, miR-29b, and miR-29c, upregulate P53 level and induce apoptosis in a P53-dependent manner [46]. They further observed that miR-29 family members directly suppress p85a, the regulatory subunit of PI3 kinase, and CDC42, both of which negatively regulate P53. Their findings provide new insights into the role of miRNAs in the P53 pathway. Given that P53 plays essential roles in modulating cellular respiration and mitochondrial functions in cancer cells as indicated by induction of downstream targets such as SCO2 and TIGAR, one could presume that miR-29 members as well as other miRNAs might modulate cancer metabolism by regulating P53.
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miRNAs As Ligaments in Metabolic Network Regulated by Oncogenes/ Tumor Suppressors Tumor metabolic regulatory network is emerging as a big arena involving many important players. The interplay between miRNAs and oncogene/tumor suppressors is complex and miRNAs may provide the missing links in the metabolic regulatory network that facilitates Warburg Effect in cancer cells Fig. (2). miR-17-92 cluster, including miR-17, miR-18a, miR-19a, miR-20a, miR19b-1 and miR-92, is described as oncomir directly activated by cMyc that binds to their promoter locus [23, 62, 63]. It is also reported that miR-17-92 cluster modulates tumor growth by inhibiting HIF-1 expression [64]. There are different targets of various miRNAs in this cluster. Tumor suppressor PTEN (phosphatase and tensin homolog) is a target of miR-17, miR-20 and miR-19, as a consequence, cancer cells will become anti-apoptotic when these miRNAs are overexpressed [65]. Interestingly, PTEN is a transcriptional target of P53, whose expression was shown to be decreased or absent in primary bladder cancer patients [66]. PTEN also has a negative effect on HIF-1 protein level and activity, presumably through an inhibition of PI3K, thereby inhibits glycolysis [47, 67]. E2F1/3 are targets of miR-17 and miR-20, but they can also upregulate miR-17-92 cluster. Taken together, the miR-17-92 cluster constitutes a complex regulatory network involving cMyc, E2Fs and other oncogenes/tumor suppressors [68]. Another example is miR-34 cluster, including miR-34a and miR34b/c, which is upregulated by P53 and plays the same roles consistent with P53 in many cancers. Of the cluster members, miR-34c can inhibit cMyc expression in response to DNA damage so as to block S-phase progression [69]. As mentioned above, miR-107 and miR-210 connect P53 with HIF-1, together stimulating glycolytic metabolism and proliferation of cancer cells. A more comprehensive overview of interplay between miRNAs and oncogenes/tumor suppressors is summarized in Fig. (2). CONCLUSION AND FUTURE PERSPECTIVES For decades, basic and clinical scientists have made tremendous efforts to combat cancers by identifying and studying alterations in cancer cells for the purpose of discovering unique targets for cancer therapy. Given that tumor cells utilize aerobic glycolysis or the Warburg Effect, during cancer development, these metabolic changes might be exploited for cancer treatments. Understanding the pathways leading to Warburg Effect in cancer cells is extremely important, particularly, the extensive interplay between small miRNAs and oncogenes/tumor suppressors that facilitates the process in cancer cells. MiRNAs are small, potent and could be great targets for therapeutics. Elucidating the unique roles and pathways by which miRNAs facilitate the Warburg effect may enable the manipulation of miRNAs and allow for their use in cancer therapy. CONFLICT OF INTEREST The author(s) confirm that this article content has no conflicts of interest. ACKNOWLEDGEMENTS The authors are grateful for Dr. Tarja Juopperi for her critical reading of this manuscript. Our work is supported in part by
MicroRNAs and the Warburg Effect: New Players in an Old Arena
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Fig. (2). The complex network system between miRNAs and oncogenes/tumor suppressors and their roles in tumor metabolism. Key oncogenes and oncomirs, such as, cMyc, HIF-1, miR-17-92 and miR-210, are indicated in red; while key tumor suppressors, such as, P53, PTEN, Let-7 and miR-23a/b are indicated in blue. The molecules embedded in gray clouds indicate miRNAs while others represent proteins. (Abbreviations: AMPK: adenosine monophosphate-activated protein kinase; PTEN: phosphatase and tensin homolog; E2Fs: E2F transcription factors; PI3K: phosphoinositide 3-kinase; GLS: glutaminase; TIGAR: TP-53 induced glycolysis and apoptosis regulator; POX/PRODH: proline oxidase/proline dehydrogenase; P5C: 1-pyrroline-5-carboxylic acid; PDK1: pyruvate dehydrogenase kinase 1; ISCU1/2: iron sulfur scaffold protein; SCO2: cytochrome C oxidase 2; -KG; alpha-ketoglutarate).
the “Strategic Priority Research Program” of Chinese Academy of Sciences (XDA01010404), National Basic Key Research Program of China (2011CBA01103), National Nature Science Foundation of China (31071257), and Maryland Stem Cell Research grant (TEDCO 90042926). ABBREVIATIONS
[3]
[4] [5] [6]
GLUT1/3
=
Glucose Transporter1/3
HK1/2
=
Hexokinase 1/2
GPI
=
Glucose-6-Phosphate Isomerase
ALDA
=
Aldehyde Dehydrogenase A
LDHA
=
Lactate Dehydrogenase A
LincRNA
=
Long Intergenic Non-Coding RNA
[9]
ceRNA
=
Competitive Endogenous RNAs
[10]
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Received: February 17, 2012
Revised: June 12, 2012
Accepted: June 12, 2012
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