Oncogene (2013) 32, 3483–3490 & 2013 Macmillan Publishers Limited All rights reserved 0950-9232/13 www.nature.com/onc

REVIEW The PGC-1/ERR signaling axis in cancer

G Deblois1, J St-Pierre1 and V Gigue`re1,2

Proliferating cells need to produce a large amount of energy and, at the same time, need to maintain a constant supply of biosynthetic precursors of macromolecules that are used as building blocks for generating new cells. Indeed, many cancer cells undergo a switch from mitochondrial to glycolytic metabolism and display a truncated tricarboxylic acid cycle to match these specific metabolic requirements of proliferation. Understanding the mechanisms by which cancer cells reprogram various metabolic pathways to satisfy their unique bioenergetic requirements has become an active field of research. Concomitantly, it has emerged that members of a family of orphan nuclear receptors known as the estrogen-related receptors (ERRs), working in concert with members of the PPARg coactivator (PGC)-1 family, act as central transcriptional regulators of metabolic gene networks involved in maintaining energy homeostasis in normal cells. Recent studies have suggested that the PGC-1/ERR transcriptional axis is also important in the metabolic reprogramming of cancer cells. This review focuses on the functional integration of the PGC-1/ ERR axis with known oncogenes and the observation that modulation of the activity of this axis can have both pro- and anti- proliferative properties.

Oncogene (2013) 32, 3483–3490; doi:10.1038/onc.2012.529; published online 3 December 2012 Keywords: nuclear receptors; metabolism; mitochondrion; Warburg effect

CANCER METABOLISM have been shown to work in concert to regulate mitochondrial An important metabolic hallmark of cancer cells is their ability to biogenesis and metabolic pathways involved in maintaining 4–7 exhibit rapid glucose consumption through aerobic glycolysis for cellular energy homeostasis. Individually, members of the energy production despite oxygen availability, a phenomenon PGC-1 and ERR families have also been implicated in various 8,9 referred to as the Warburg effect.1 Although apparently an oncogenic processes. inefficient process, cancer cells rely on sustained glycolysis not This review illustrates how modulation of the activity of the only for rapid energy production but also for the use of carbon PGC-1/ERR transcriptional axis influences the expression of sources to generate intermediate metabolites required for the metabolic gene networks in cancer cells. We also present synthesis of nucleic acids. Moreover, the tricarboxylic acid (TCA) evidences that interplay between the PGC-1/ERR axis and specific cycle remains functional in most cancer cells and produces oncogenes can contribute to the metabolic reprogramming of intermediates for the biosynthesis of structural precursors like cancer cells and of the tumor microenvironment. amino acids and fatty acids necessary for making new cells. Since most pyruvate generated from glycolysis is converted to lactate by LDHA-B in cancer cells, the TCA cycle functions as a truncated PGC-1S AND ERRS: A POTENT FUNCTIONAL RELATIONSHIP cycle that needs to be replenished with intermediates in order to The ERR family of nuclear receptors is named so because it was function, a process called anaplerosis. Cancer cells utilize originally discovered during a cloning exercise aimed at identify- glutamine metabolism for feeding the diverted TCA cycle, thus ing steroid hormone receptors bearing structural similarity with providing the carbon sources necessary for making substrates like the estrogen receptor (ERa).10 The family includes three isoforms, ketoglutarate and oxaloacetate used for amino-acid synthesis and 2,3 ERRa [NR3B1], ERRb [NR3B2] and ERRg [NR3B3], that possess all citrate for lipid synthesis. Notably, cancer cells also use the functional domains characteristic of members of the nuclear glutaminolysis and the pentose phosphate pathway to generate receptor superfamily including those of the classic estrogen abundant reductive power (NADPH) for fatty acid synthesis and receptor.11 However, these orphan receptors do not bind natural cellular detoxification, two important processes to maintain cell 2 estrogens nor do they participate in classic estrogen physiology. proliferation. Instead, functional genomic studies as well as phenotypic analyses Therefore, investigating how cancer cells reprogram their of cells, tissues and whole organisms in which the expression of metabolism to satisfy their bioenergetic requirements and how the ERR isoforms was manipulated revealed an essential role for this process can be reversed to block tumor growth has become a these transcription factors in regulating the expression of very active field of research. During the last decade, members of metabolic genes either directly or indirectly.4,6,12 The two distinct families of transcriptional regulators, the orphan transcriptional activity of the ERRs is ligand-independent and nuclear receptors known as the estrogen-related receptors (ERRs) highly relies on the presence of coregulatory proteins, most and the transcriptional coactivators referred to as the peroxisome notably that of PGC-1a and PGC-1b.13–18 The PGC-1s likely act as proliferator activated receptor g (PPARg)-coactivator-1s (PGC-1s), surrogate protein ligands for the ERRs in regulating the expression

1Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada and 2Departments of Medicine and Oncology, McGill University, Montreal, Quebec, Canada. Correspondence: Professor V Gigue`re, Goodman Cancer Centre, McGill University, 1160 Pine Avenue West, Room McIntyre 710, Montreal, Quebec, Canada H3A 1A3. E-mail: [email protected] Received 9 August 2012; revised 15 October 2012; accepted 15 October 2012; published online 3 December 2012 Metabolic reprogramming of tumor cells G Deblois et al 3484 of mitochondrial genes and of other gene sets involved in the Gleason score and with reduced survival rates. In contrast, the maintenance of energy homeostasis as well as glucose and lipid expression levels of both ERRb and ERRg surveyed by immuno- metabolism.19 While PGC-1a was originally discovered during a histochemistry were found to be low in tumors with reduced search for proteins able to interact with the nuclear receptor survival rates, suggesting that they act as favorable markers in PPARg,20 the coactivator can interact with a very diverse set of prostate tumors. Finally, the gene and protein expression levels of transcription factors including NRF-1, GABPA, YY1 and several ERRa in uterine tumors are inconsistent, with reports of both low other nuclear receptors.7,21 In particular, the PGC-1a protein and high expression levels associated with myometrial invasion. encodes three LxxLL motifs (L1–L3) that generally function as The expression of ERRg was found high in uterine tumors versus docking sites for nuclear receptors. Indeed, motif L2 allows adjacent normal tissue and to correlate with myometrial invasion. interaction of PGC-1a with a wide range of nuclear In a manner similar to the ERRs, the PGC-1s are highly expressed receptors.14,17,22,23 In contrast, the more atypical L3 motif acts as in tissues with high energy demand and PGC-1a expression is a high affinity specific anchor for the ERRs.14,17,24 Interestingly, it increased upon exposure to diverse physiological stresses.39 has been shown that PGC-1a L2–L3 mutants engineered to However, less is known about the expression of PGC-1 isoforms specifically interact with the ERRs have similar transcriptional in human tumors (Table 1). In general, the expression of PGC-1a is outputs to that of wild-type PGC-1a.25 This observation suggests reduced in most tumors compared with normal tissue, including that the mechanism privileging specific physical interactions those originating from the breast, colon, ovaries and liver. between the PGC-1s and the ERRs has clear biological Nevertheless, a report suggested that while the expression of significance.21,25,26 Indeed, several studies have shown a PGC-1a is not significantly different in breast tumors versus functional codependency between the PGC-1s and the ERRs for normal adjacent tissues, a decrease in PGC-1a in tumors was their ability to control the expression of target genes.4,18,27,28 associated with a poor prognosis.40 In contrast, PGC-1a levels were shown to be elevated in endometrial cancer and renal tumors. It should be noted that the expression levels of PGC-1a are generally EXPRESSION OF ERRS AND PGC-1S IN HUMAN TUMORS low and exhibit dynamic regulation by many environmental The three ERR isoforms are widely but differentially expressed in factors. These factors could contribute to the variability and to the embryonic and adult tissues.11 The expression pattern of the three technical challenges in assessing PGC-1a expression in human ERR isoforms is characterized by high levels in tissues with greater tumors. The levels of PGC-1b in human tumors have yet to be energy demands such as the heart, skeletal muscles and examined in a meaningful manner. kidneys.29–33 The widespread expression profile of ERRs in A recent comprehensive study examining genetic alteration in normal tissues combined with the observation that the ERRs can 510 human breast tumors revealed significant amplification and dictate the fate of cells of various origins34–37 advocates that deletion in the genomic loci containing the genes ESRRA deregulation of ERR transcriptional signaling could play a role in (11q13.1), ESRRB (14q24) and ESRRG (1q36) coding for all three various types of cancer. Indeed, altered expression of all three ERR isoforms of ERRs, particularly in the luminal A and B subtypes.41 isoforms has been reported in human tumors of various origins Similarly, both amplification and deletion of the PPARGC1B locus (Table 1 and references therein). The expression of ERRa has (5q23) and deletion of the PPARGC1A locus (4p14–16) have been mostly been studied in breast tumors where it is often highly observed in a significant number of breast tumors. However, this expressed. The expression of ERRa in samples from various study did not report any mutation or epigenetic abnormality cohorts of breast cancer patients correlates positively with the associated with these genes. Nevertheless, in a previous study, expression of the oncogene ERBB2 and of the coactivator SRC-3 genetic variants in PPARGC1A and PPARGC1B have been reported (also known as Amplified in Breast Cancer 1, AIB1), as well as with in breast tumors and were associated with familial breast cancer node status, increased risk of recurrence, resistance to the susceptibility.42 antiestrogenic drug tamoxifen and metastatic status at both the protein and mRNA expression levels (Table 1). In some studies, the expression of ERRa is also inversely correlated to that of ERa and EXPRESSION OF PGC-1/ERR TARGET GENES IN HUMAN the progesterone (PR) receptors, which are considered good TUMORS prognostic markers in breast cancer. Taken together, the patterns The vast majority of the target genes of the PGC-1/ERR axis have of expression of these factors indicate that ERRa is an unfavorable been identified using functional genomics in various cell lines. prognostic marker in breast tumors. However, on its own, the Intersecting the PGC-1/ERR target genes with gene expression mRNA expression of ERRa in breast tumor microarray data sets is data from human breast tumors validated their biological in general not a good predictor of patient survival.38 ERRb relevance. Indeed, examination of the expression profile of ERRa expression was also detected in breast tumors and associates with direct target genes identified by ChIP-on-chip in MCF-7 and SkBr3 that of ERb but the implications of these observations are not cells in expression data from cohorts of human breast tumor clear. The expression of ERRg was also reported as high in some samples separates ERRa target genes into four clusters that breast tumor samples and its expression was positively associated recapitulate the previously established breast tumor subtypes.43 with PR and ERBB4 expression, lymph node-negative status as well This result not only implies that ERRa signaling is breast tumor as with increased ERa signaling, all occurrences considered as subtype specific but also suggests that ERRa could contribute to good prognostic markers. Therefore, in contrast to ERRa, ERRg is the establishment of intra-tumor heterogeneity by regulating considered a favorable marker in breast tumors and accordingly, distinct sets of genes, a phenomenon that is linked to clinically the expressions of both receptors are inversely correlated. important aspects of human cancers such as prognosis, risk of In ovarian tumors, the expression of ERRa correlates with high metastasis and therapeutic response.44 In addition, the study by grade and with the presence of the CA-125 antigen and is thus Deblois et al.43 identified 86 ERRa target genes whose expression associated with reduced survival rates (Table 1). While the in cohorts of human breast tumor samples significantly associated expression of ERRg was also found to be high in ovarian tumors with clinical outcome. Of note, the expression of several genes versus normal adjacent tissue, its expression correlates with FIGO included in this prognosis-associated signature were significantly stage and, similarly to breast cancer, with improved survival rates. affected by treatment with the ERRa inverse agonist XCT-790, In contrast to most cancers, ERRb expression can be detected in suggesting that the expression of ERRa targets that are important ovarian tumors but only at low levels and without correlation with to breast cancer etiology could be acquiescent to pharmacologic disease status or patient survival. In prostate tumors, ERRa is regulation. Using a similar approach, Chang et al.38 examined the highly expressed by immunohistochemistry and correlates with expression patterns of ERRa target genes identified upon

Oncogene (2013) 3483 – 3490 & 2013 Macmillan Publishers Limited Metabolic reprogramming of tumor cells G Deblois et al 3485 Table 1. Expression of ERR and PGC isoforms in human tumors

Measurement Isoform Expression Association Implication References

Breast cancer RT À PCR ERRa High ERa À ,PRÀ , ERBB2 þ Unfavorable marker Ariazi et al.64 IHC ERRa Positive Increased risk of recurrence Prognostic factor Suzuki et al.77 RT À PCR ERRa High Type node status ERa À Decreased in Fradet et al.78 metastasis free survival RT À PCR and IHC ERRa High AIB1 Increased ERRa activity Heck et al.79 in ERa À tumors RT À PCR and IHC ERRa High versus normal c-Myc, Ki67, aromatase None Jarzabek et al.80 RT À PCR ERRb Positive ERb Unclear Ariazi et al.64 RT À PCR ERRg High PR þ , ERBB4 þ Favorable marker Ariazi et al.64 IHC ERRg High Lymph node negative Increased ER signaling Ijichi et al.81 RT À PCR PGC-1a Low None Poor outcome Jiang et al.40 IHC PGC-1a Low None None Watkins et al.82

Ovarian cancer RT À PCR ERRa High versus normal CA-125 Grade FIGO stage Reduced survival Sun et al.83 RT À PCR ERRb Low None None Sun et al.83 RT À PCR ERRg High versus normal FIGO stage Increased survival Sun et al.83 RT À PCR ERRa High Grade Reduced survival Fujimoto et al.84 RT À PCR PGC-1a Low versus normal Apoptotic pathway None Zhang et al.85

Uterine cancer RT À PCR and IHC ERRa High Myometrial invasion Prognostic factor Fujimoto et al.84 RT À PCR and IHC ERRa Lower versus normal Myometrial invasion Prognostic factor Gao et al.86 RT À PCR and IHC ERRg Higher versus normal Myometrial invasion Prognostic factor Gao et al.86

Prostate cancer IHC ERRa Higher versus benign Gleason score Reduced survival Stein et al.87 IHC ERRb Lower versus benign ERRg Reduced survival Fujimura et al.88 IHC ERRg Lower versus benign ERRb Reduced survival Fujimura et al.88

Colorectal cancer IHC ERRa Higher versus normal TNM stages Prognostic factor Cavallini et al.89 IHC ERRg Same versus normal None None Cavallini et al.89 RT À PCR PGC-1a Low versus normal None None Feilchenfeldt et al.90

Liver cancer RT À PCR PGC-1a Low versus normal None None Ba et al.91

Endometrial cancer Western blotting PGC-1a High versus normal None None Cormio et al.92

Renal cancer RT À PCR PGC-1a High FLNC mutations None Klomp et al.93 Abbreviations: ERR, estrogen-related receptor; IHC, immunohistochemistry; PGC, PPARg coactivator. coactivation with the ERR-selective PGC-1a mutant in a human led to the definition of the ‘ERR regulon’ in mouse liver.13 The primary mammary epithelial cell line, throughout clinical data sets. results of genome-wide location analyses were often correlated This study showed that the expression of a subset of the genes with expression data showing that functional binding of ERRs to regulated by the PGC-1/ERR axis is associated with shorter disease- promoters is associated with the modulation of expression of the free survival in patients. In agreement with the work of Deblois metabolic target genes and that PGC-1a and/or PGC-1b were et al.,43 this signature related to the PGC-1/ERR activity predicts required for the induction of these target genes. the ability of XCT-790 to inhibit the proliferation of breast cancer Similar results were obtained for ERRa in human cancer cell cells in culture. Therefore, while the sole expressions of ERRs or lines. ChIP-on-chip experiments by Deblois et al.43 identified a PGC-1s are not systematically predictive of outcome in tumors, total of 1026 ERRa binding sites in the extended promoter regions interrogation of the expression of their target genes is more of target genes in MCF-7 and SKBr3 human breast cancer cells. informative for predicting outcome. The genes associated with these binding events are significantly enriched for various metabolic-related functions including oxidative phosphorylation, TCA cycle and aerobic respiration.43 THE PGC-1/ERR AXIS TARGETS METABOLIC GENES AND Of particular interest, ERRa was found to bind to the promoters REGULATORS IN CANCER CELLS and to regulate the expression of metabolic genes that have been A decade after the initial identification of Acadm as the first target previously linked to cancer development and progression gene of ERRa,45,46 functional genomic experiments in mouse including genes involved in glycolysis (for example, LDHA, PGM1, heart, liver, kidneys and embryonic stem cells have irrevocably PFKM), the TCA cycle and mitochondrial metabolism (for example, established the PGC-1/ERR axis as the main regulator of gene SDHB, IDH1, IDH2), OXPHOS (for example, several components of networks implicated in mitochondrial biogenesis and energy mitochondrial complex I, COX1), amino-acid metabolism (for metabolism.4,5 Indeed, in normal cells, ERRa was found to bind to example, PHGDH, GLS2) and lipid synthesis (for example, ACLY, the promoters of virtually all genes involved in glycolysis, pyruvate FASN).43,47–49 Likewise, functional location analyses experiments metabolism, TCA cycle and of most genes encoding the five revealed recruitment of PGC-1b to the promoter of target genes complexes of the oxidative phosphorylation pathway. The shared with ERRa and involved in regulating all aspects of energy all-embracing control of metabolic target genes exerted by ERRa metabolism in breast cancer cells (Figure 1). Analysis of microarray

& 2013 Macmillan Publishers Limited Oncogene (2013) 3483 – 3490 Metabolic reprogramming of tumor cells G Deblois et al 3486

Figure 1. ERRa and PGC-1b share target genes in breast cancer cells. (a) Venn diagram of binding sites shared by ERRa and PGC-1b in the promoters of their target genes as assessed by ChIP-on-chip and ChIP-Seq experiments in SKBr3 cells. De novo motif finding using the MEME suite (http://meme.sdsc.edu/meme/intro.html) identified the ERRE as the most enriched binding site in the overlapping segments (P-value: 7.2 e À 07). (b) Representative binding profiles of ERRa (green) and PGC-1b (purple) on the promoter of ACO2. (c) Enriched canonical pathways for target genes shared by ERRa and PGC-1b in human breast cancer cells (Ingenuity Systems Pathway Analysis, http://www.ingenuity.com/).

expression data in MCF-7 breast cancer cells transduced with an mammary epithelial cells.52 The levels of the ERBB2 protein are adenovirus encoding a PGC-1a mutant that selectively activates themselves regulated by nutrient availability, including glucose.53 the ERRs also showed that the majority of genes regulated in this Functional genomics studies in breast cancer cells have also context are involved in various aspects of energy metabolism and shown that ERRa can regulate the expression of genes encoding in the response to oxidative stress.25 Disruption of ERRa activity by proteins involved directly or indirectly in the control of metabolic a specific antagonist molecule (compound A) in both MCF-7 and genes processes like c-Myc, c-Jun, p53, VEGF (vascular endothelia BT-20 human breast cancer cell lines also led to modulation of growth factor) and b-catenin.43 The list of ERR target genes also gene networks involved in energy metabolism.50 includes several other genes involved in growth factor signaling, The PGC-1/ERR axis was found to regulate important genes kinases and adaptor proteins that have also been implicated in the involved in various tumorigenic processes than can also mediate metabolic reprogramming of cancer cells.25,43 metabolic reprogramming. For instance, ERRa and PGC-1b bind to the promoters and enhancers of genes located in the ERBB2 amplicon on human chromosome 17q12–21 and regulate their THE PGC-1/ERR AXIS AND BIOENERGETIC REGULATION OF expression in breast cancer cells and in mammary tumors in CANCER CELLS mice.51 ERBB2 expression stimulates glucose uptake, NADPH As mentioned previously, reprogramming of cancer cell metabo- production by the pentose phosphate pathway and fatty acid lism appears to be fundamental to the establishment and oxidation, which result in a reduction in oxidative stress in maintenance of tumorigenesis. Recent studies have highlighted

Oncogene (2013) 3483 – 3490 & 2013 Macmillan Publishers Limited Metabolic reprogramming of tumor cells G Deblois et al 3487 a dynamic interaction between glycolysis, mitochondrial function NADPH. By regulating the expression of cell detoxification and biosynthetic pathways in cancer.54 Upregulation of enzymes enzymes like SOD2 and GSDM1 and enhancing NADPH controlling glycolysis, in particular expression of PKM2, a splicing production through glycolysis and glutamine metabolism, the variant of pyruvate kinase found in muscle, is often observed in PGC-1/ERR axis can provide growing cells with an anti-oxidant cancer cells.55 ERRa and ERRg bind to the promoter and regulate defense mechanism and control the oxidative stress damage the expression of these glycolytic enzymes in both normal tissues induced on proliferating cells and cancer cell lines.13,30,32,43,56–58 In normal tissues, the presence of ERRa is indeed necessary for carbohydrate-based energy 59 production in the heart in response to cardiac stress and in PGC-1b IS A KEY COMPONENT OF PGC-1/ERR AXIS IN CANCER Drosophila to direct a metabolic switch to glycolysis, pentose CELLS phosphate pathway and other aspects of carbohydrate 12 As introduced above, lower expression of PGC-1a in tumors was metabolism to support developmental growth. ERRa is 40 indispensable for the ability of the hepatocellular carcinoma associated with poor prognosis while the expression of PGC-1b HepG2 cell line to switch from oxidative to glycolytic metabolism but not PGC-1a or PPRC1, the third member of the PGC-1 family, correlated with the expression of ERRa in a large panel of breast when mitochondrial oxidative phosphorylation is unable to meet 38 their energy demand.13 It is therefore apparent that ERRa cancer cell lines. These observations suggest that the activity of possesses the necessary functional attributes to induce the the PGC-1/ERR axis in cancer cells might be driven by the PGC-1b Warburg effect in cancer cells. isoform. Indeed, evidence is rapidly accumulating that points to Nevertheless, the involvement of the PGC-1/ERR axis in the PGC-1b as a key component of the PGC-1/ERR axis in cancer cells. metabolic reprogramming of cancer cells likely exceeds the First, recruitment of PGC-1b, but not that of the SRC-3 (AIB1) coactivator, was observed at genomic regions occupied by ERRa control of glycolysis. Indeed, ChIP-on-chip data in breast cancer 43 cells revealed binding of ERRa to the extended promoter of the in SKBr3 cells. Second, ChIP-on-chip experiments examining enzymes involved in the control of glutamine metabolism43 PGC-1b recruitment at specific genomic locations showed that (unpublished data), while activation of the PGC-1/ERR axis with an PGC-1b recruitment occurs at sites shared with ERRa in breast ERR-specific mutant of PGC-1a supports functional regulation of SKBr3 cells and close to genes associated with metabolic these target genes.25 Moreover, the recruitment of ERRa to the processes (Figure 1). Recruitment of PGC-1b at common sites promoter of all the enzymes involved in the TCA cycle, lipid and was lost upon depletion of ERRa while knockdown of PGC-1b led amino-acid synthesis and the control of their expression by ERRa to reduced expression of ERRa target genes, including those located within the ERBB2 amplicon. Knockdown of PGC-1b also in breast cancer cells could contribute to the anaplerotic process 51 that sustains the truncated TCA cycle and to the biosynthesis of led to a significant decrease in SKBr3 cell proliferation. Third, building blocks.25 Therefore, reprogramming of cancer cell PGC-1b is a component of a feed forward loop dictating the transcriptional output of the distinct ERR isoforms in human and metabolism by the PGC-1/ERR axis likely extends beyond 57 sustaining the Warburg effect. This dual activity of ERRa reflects murine mammary tumor cells. This regulatory loop includes miR- its complex involvement in regulating multiple aspects of cancer 378*, that is embedded within the gene encoding PGC-1b and cell metabolic reprogramming. targets ERRg to inhibit its expression. Increased expression of miR- In normal tissues, the presence of ERRg is required for the heart 378* correlates with progression of breast cancer toward more advanced stages of the disease. Since miR-378* and PGC-1b were to switch from fetal carbohydrate metabolism to a post-natal 57 program enabling fatty acid oxidation as the main energy shown to be coexpressed, it can be inferred that PGC-1b source.58 The dependency on ERRg for adult heart development expression follows the same trend during breast cancer supports a role as a regulator of the switch towards oxidative progression. Fourth, knockdown of PGC-1b in SKBr3 cells also metabolic functions in cancer cells as well, a metabolic phenotype led to a decreased expression of PGC-1/ERR target genes associated with better prognosis. Indeed, inhibition of ERRg associated with an unfavorable outcome as well as a significant reduction in the growth of these cells,38 as previously expression by miR-378* in both human and murine mammary 43,51 cancer cells leads to a reduction in TCA cycle gene expression and observed. Taken together, these results indicate a prominent oxygen consumption with a concomitant increase in lactate role for PGC-1b in determining the activity of the PGC-1/ERR axis production and cell proliferation.57 Furthermore, ectopic in human breast tumors. expression of ERRg in mammary carcinoma cells enhances oxidative metabolism and inhibits the growth of tumor xenografts in vivo.60 ONCOGENIC REGULATION OF THE PGC-1/ERR AXIS The metabolic state associated with cell proliferation involves The activity of the PGC-1/ERR axis is clearly linked to the cancer oxidative metabolism and the consequent production of ROS phenotype, indicating that oncogenic signals could be involved in (reactive oxygen species) that are detrimental to the cells and can the regulation of the expression or activity of its components. induce caspase-mediated apoptosis.61 Tumor cells can evade this Early studies showed that the expression of ERRa correlates with protection mechanism and therefore ensure continued the presence of ERBB264 and that the epidermal growth factor/ proliferation by activating detoxification mechanisms that ERBB2 signaling axis regulates the transcriptional activities of remove the accumulated ROS. Components of the ERR/PGC axis ERRa.65,66 However, very little is known about the regulation of the have been shown to bind to the promoter of and to regulate the expression of ERRa in cancer cells. On the other hand, the expression of a number of enzymes involved in the response to expression of PGC-1b has been shown to be dependent on c-Myc oxidative stress such as superoxide dismutase (SOD2) and of the in renal carcinoma cells67 and likewise, induction of c-Myc detoxification enzyme glutathione S-transferase M1 (GSDM1) in expression by IGF-1 and heregulin precedes an increase in PGC- breast cancer cells.25,43 In addition, increased levels of ERRa and 1b mRNA in MCF-7 breast cancer cells.38 In addition, treatment of PGC-1a, accompanied by enhanced protection against the these cells with a c-Myc inhibitor prevents the induction of PGC-1b deleterious effects of oxidative stress, have been observed in a mRNA by IGF-1 and heregulin, and c-Myc binds to a regulatory model of breast cancer brain metastasis.62 It should also be noted region within the first intron of the PGC-1b gene.38 Furthermore, that PGC-1a has been shown to be a powerful regulator of ROS binding of c-Myc to this site is upregulated upon treatment with metabolism in the context of a model of neurodegenerative IGF-1 or heregulin38 while knockdown of ERBB2 in BT-474 breast disease.63 The levels of NADPH are also important for this process cancer cells inhibits PGC-1b expression.57 These results are since the detoxification process by glutathione reductase requires consistent with the knowledge that the ERBB2 signaling

& 2013 Macmillan Publishers Limited Oncogene (2013) 3483 – 3490 Metabolic reprogramming of tumor cells G Deblois et al 3488 pathway can regulate c-Myc expression at the transcriptional and translational levels.68,69 However, control of c-Myc expression is multifaceted and therefore it should not be expected that c-Myc- directed increase in activity of the PGC-1/ERR axis is limited to ERBB2-positive tumors. Indeed, differential ERRa transcriptional activity can be observed in all subtypes of breast cancer.43

THE PGC-1/ERR AXIS IN INVASION, ANGIOGENESIS AND METASTASIS One of the hallmarks of aggressive tumors is their metastatic ability dictated by their invasion and migration potential as well as their capability to establish tumor vascularization. The glycolytic state that prevails in tumor cells reflects a metabolic profile known to favor tumor angiogenesis, invasion and migration.70 Since ERRa could contribute to the metabolic reprogramming of cancer cells, it can be envisioned that it also affects metastatic potential of these cells. In normal tissues, decreased expression of ERRa was shown to affect cell migration during zebrafish gastrulation in vivo.71 It also affects breast cancer cell migration in vitro, albeit without affecting proliferation rates.25 The absence of ERRa is also able to impair tumorigenic potential in aggressive breast cancer cells xenograft in nude mice.25 These observations are supported by the finding that ERRa and its coactivator PGC-1a bind to the promoter of and regulate the expression of VEGF, an important factor involved in tumor angiogenesis and invasion.72,73 The PGC-1/ERR axis has also been shown to be a potent inducer of VEGF53 and to promote 72 angiogenesis in muscle. In addition, the kinase suppressor Figure 2. Schematic representation of the potential involvement of of ras1 (KSR1) is able to regulate ERRa and PGC-1a to promote the PGC-1/ERR axis and its specific components on metabolic oncogenic ras-dependent and anchorage-independent growth of output and its consequences on oncogenic progression. cancer cells.74 ERRa has also been shown to regulate the expression of HIF in breast cancer cells and to associate with the HIFa/b heterodimer to promote its transcriptional activity on angiogenic and PGC-1/ERR axis in tumor development will need to be addressed in migratory target genes like VEGF.75 ERRa is also thought to cooperate the future in order to obtain a more comprehensive view of the with HIF to induce the metabolic reprogramming towards the impact of this axis on tumor development. In particular, it will be metastatic-promoting glycolytic state in tumor cells.75 The PGC-1/ERR central to decipher the particular roles of the specific PGC-1/ERR pairs axis also regulates the expression of WNT11, a process that involves in tumors, mostly in setting the metabolic status of cancer cells. Such ERRa in a transcriptional complex with b-catenin.76 Ablation of knowledge would further allow to better assessing which cancers either ERRa or b-catenin expression decreases the migratory capacity would best benefit from pharmacological targeting of the specific of cancer cells of various origins, an observation that provides PGC-1/ERR complexes. biological significance to this ERRa/b-catenin/WNT11 signaling While several oncogenes and tumor suppressors have been pathway. In addition, functional genomics has identified ERRa implicated in the regulation of cancer cell metabolism, the target genes involved in invasion and migration and in promoting PGC-1/ERR axis has recently emerged as one of the key, and tumor vascularization such as FGF and CXCR4.51 ERRg,butnot possibly the most significant player in the process leading to the PGC-1a, was shown to directly regulate the expression of E-cadherin reprogramming of metabolism in tumor cells. Being central to this and to promote a genetic program characteristic of mesenchymal- process and amenable to pharmacologic manipulation, the PGC-1/ to-epithelial transition.60 This observation provides further evidence ERR axis provides a unique therapeutic opportunity to reprogram, that the activity of the different components of the PGC/ERR axis in a comprehensive manner, the networks of metabolic pathways can have distinct transcriptional output. The promotion of whose activities are deregulated by cancer genes. mesenchymal-to-epithelial transition by ERRg might be related to the correlation of its expression with better prognosis in several types of cancer. CONFLICT OF INTEREST The authors declare no conflict of interest. CONCLUDING REMARKS Studies reviewed herein clearly show that modulation of cellular ACKNOWLEDGEMENTS energy metabolism by the PGC-1/ERR transcriptional axis plays a major role in the process of tumorigenesis. In normal cells, the activity of the This work was supported by grants from the Canadian Institutes for Health Research PGC-1/ERR axis can be used to increase cellular metabolism, to support to VG (MOP-64275) and JSt-P (MOP-106603) and a Program Project Grant from the Terry Fox Foundation to VG and JSt-P (TFF-116128). GD was supported by a the growth of rapidly dividing cells, to direct metabolic programs predoctoral traineeship award (W81XWH-10-1-0489) from the US Department of necessary for cell differentiation and to maintain cellular energy Defense Breast Cancer Research Program. JSt-P is an FRSQ research scholar. homeostasis in differentiated cells. Indeed, the action of the PGC-1/ERR axis can have both proliferative and anti-proliferative outcomes, which are likely dependent on the composition of the PGC-1/ERR complexes REFERENCES present in these cells. In cancer cells, the activity of the PGC-1/ERR axis 1 Warburg O. On respiratory impairment in cancer cells. Science 1956; 124: 269–270. is further influenced by oncogenic signals and can thus be re-directed 2 DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB. The biology of to induce metabolic programs favoring or attenuating cell growth and cancer: metabolic reprogramming fuels cell growth and proliferation. 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