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The Role of Pgc1a in Cancer Metabolism and Its Therapeutic Implications Zheqiong Tan1,2,3, Xiangjian Luo1,2,3, Lanbo Xiao1,2,3, Min Tang1,2,3, Ann M

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The Role of Pgc1a in Cancer Metabolism and Its Therapeutic Implications Zheqiong Tan1,2,3, Xiangjian Luo1,2,3, Lanbo Xiao1,2,3, Min Tang1,2,3, Ann M Published OnlineFirst April 15, 2016; DOI: 10.1158/1535-7163.MCT-15-0621 Review Molecular Cancer Therapeutics The Role of PGC1a in Cancer Metabolism and its Therapeutic Implications Zheqiong Tan1,2,3, Xiangjian Luo1,2,3, Lanbo Xiao1,2,3, Min Tang1,2,3, Ann M. Bode4, Zigang Dong4, and Ya Cao1,2,3 Abstract PGC1a is a transcription factor coactivator that influences a controlled by oncogenes and transcription factors. PGC1a and majority of cellular metabolic pathways. Abnormal expression of these molecules can form signaling axes that include PML/ PGC1a is associated with several chronic diseases and, in recent PGC1a/PPARa, MITF/PGC1a, and PGC1a/ERRa, which are years, it has been shown to be a critical controller of cancer important in regulating metabolic adaptation in specific cancer development. PGC1a acts as a stress sensor in cancer cells and types. Some of these PGC1a-associated pathways are inherently can be activated by nutrient deprivation, oxidative damage, and activated in cancer cells, and others are induced by stress, which chemotherapy. It influences mitochondria respiration, reactive enable cancer cells to acquire resistance against therapy. Notably, oxygen species defense system, and fatty acid metabolism by certain therapeutic-resistant cancer cells are addicted to PGC1a- interacting with specific transcription factors. The characteristic dependent metabolic activities. Suppression of PGC1a expression traits of PGC1a in maintaining metabolic homeostasis promote resensitizes these cells to therapeutic treatments, which implicates cancer cell survival and tumor metastasis in harsh microenviron- PGC1a as a promising target in cancer molecular classification ments. Not only does PGC1a act as a coactivator, but is also itself and therapy. Mol Cancer Ther; 15(5); 774–82. Ó2016 AACR. Introduction mitochondrial oxidative phosphorylation (OxPhos) by coactivat- ing nuclear respiratory factor 1 and estrogen-related receptors (ERR; Metabolic reprogramming is considered to be a hallmark of refs.18, 19). It has been identified to stimulate fatty acid oxidation cancer (1). Glycolysis, mitochondrial respiration, glutaminolysis, (FAO) through interactions with several transcription factors and fatty acid metabolism are important participants in cancer including sirtuin 1 (SIRT1), PPARs, and hepatocyte nuclear factor development (2–6). These processes provide cancer cells with an 4(20–25), and PGC1a also increases autophagy and thermogen- adaptable metabolic feature and afford survival opportunities for esis through transcription factor EB and uncoupling protein-1, cancer cells undergoing stress (7–9). Among the numerous reg- respectively, under stress condition (26–30). In addition, it has ulators or mediators of cancer metabolism, PPARg coactivator-1 been shown to protect cells against oxidative damage through alpha (PGC1a) is emerging as an essential controller of multiple nuclear factor erythroid 2 (Nrf2) and forkhead box O3 (31–33). metabolic pathways (10, 11). In all of these instances, PGC1a functions as a necessary adaptor PGC1a is strongly activated by conditions causing energy lim- for cells to maintain metabolic balance under harsh situations, and itation, including cold, exercise, and fasting, and is particularly it plays a protective role in preventing chronic disease, such as abundant in tissues demanding large energy consumption (12– skeletal muscle atrophy, heart failure, neurodegeneration, obesity, 14). Once activated, PGC1a interacts with several transcription diabetes, and hepatic steatosis, and some of these diseases are factors and affects various biologic activities under normal phys- predisposing factors for cancer initiation (10, 11, 34, 35). Recently, iologic conditions (15). Induced by exercise, PGC1a can promote a several advances have shown that PGC1a expression is tightly functional fiber switch toward more oxidative types in skeletal associated with cancer progression (10, 11). The exceptional ability muscle cells by interacting with muscle-specificmyocyteenhancer of PGC1a in manipulating cellular metabolism enables cancer cells factor 2 family transcription factors (16, 17). PGC1a also facilitates to thrive under a constantly fluctuating energy status, and highlights the importance of PGC1a in effective cancer therapy (36). 1Cancer Research Institute, Xiangya School of Medicine, Central South University, Hunan, China. 2Key Laboratory of Chinese Ministry of Structure and Regulation Mechanism of Education, Central South University, Hunan, China. 3Key Laboratory PGC1a of Carcinogenesis of Chinese Ministry of Public Health, Central South University, Hunan, China. 4The Hormel Institute, University of Minne- The PGC1a gene is located on chromosome 4 in human and sota, Austin, Minnesota. encodes a protein containing 798 amino acids (29). When acti- Corresponding Author: Ya Cao, Cancer Research Institute, Xiangya School of vated, PGC1a can be recruited as a transcriptional coactivator to Medicine, Central South University, Xiangya Road 110, Changsha 410078, China. subsequently dock or bind with transcription factors or nuclear Phone: 860-731-8480-5448; Fax: 860-731-8447-0589; E-mail: receptors (NR; refs.15, 37). The N-terminal activation domain and [email protected] LXXLL motifs of PGC1a interact with various transcription factors doi: 10.1158/1535-7163.MCT-15-0621 (19, 37, 38). Proteins, such as CREB-binding protein, p300 Ó2016 American Association for Cancer Research. and steroid receptor that acetylate histones, can be sequentially 774 Mol Cancer Ther; 15(5) May 2016 Downloaded from mct.aacrjournals.org on September 28, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst April 15, 2016; DOI: 10.1158/1535-7163.MCT-15-0621 PGC1a in Cancer Metabolism and Its Therapeutic Implications recruited to the PGC1a transcriptional activator complex, to Ectopic expression of PGC1a has been observed in several cancer remodel the chromatin structure and provide optimal biochem- types (50–53), and it is regulated by several oncogenes and sig- ical conditions for target gene transactivation (39). The C terminal naling pathways (Fig. 1; refs.54–57). Similar to its normal phys- of PGC-1a is believed to recruit the thyroid receptor–associated iologic functions, PGC1a primarily regulates mitochondrial respi- protein/vitamin D receptor–interacting protein/mediator com- ration and detoxification of reactive oxygen species (ROS) in cancer plex that facilitates transcription initiation and interferes with cells through specific signaling pathways and transcription factors RNA processing through Ser/Arg-rich or RNA-binding domains (Table 1). In addition, the involvement of PGC1a in regulating (40, 41). FAO and glucose- or glutamine-derived lipogenesis in cancer cells Notably, PGC1a is controlled by several posttranslational has become clearer in recent years (Fig. 2; refs.49, 51, 58). modifications. Because PGC1a is markedly sensitive to cellular energy status, it is tightly regulated by stress sensors such as AMP- MITF/PGC1a Axis in Melanoma activated protein kinase (AMPK) and SIRT1. Both AMPK-medi- Among all its functions, PGC1a-dependent regulation of ated phosphorylation and SIRT1-mediated deacetylation activate OxPhos is best studied in cancer, especially in melanoma. On PGC1a under energy deprivation conditions (42, 43). In addi- the basis of PGC1a expression levels, melanomas have been tion, the p38 MAPK stabilizes the PGC1a protein by increasing its defined into two subsets with different biologic phenotypes phosphorylation state (44). On the other hand, methylation of (53, 59, 60). The PGC1a-positive cells exhibit elevated mitochon- the arginine residues at the C-terminal region by protein arginine drial oxidative metabolism and substantial ROS detoxifying methyltransferase 1 (PRMT1) decreases PGC1a stability whereas capacities. In contrast, the PGC1a-negative cells are dependent phosphorylation of PGC-1a by Akt/protein kinase B and SUMOy- on glycolysis for survival and are more sensitive to ROS-induced lation at the conserved lysine residue 183 attenuate PGC1a apoptosis (53). In this context, PGC1a is transactivated by the activity (44–46). These diverse posttranslational modifications oncogenic melanocyte lineage-specification transcription factor direct PGC1a to different target genes. In addition to posttrans- (MITF), and the PGC1a-negative cells seldom express MITF (57, lational modifications, PGC1a is also influenced by cellular þ 61). These findings indicate that melanomas classified by the calcium (Ca2 ) and cyclic adenosine monophosphate signaling expression of MITF/PGC1a have different metabolic capacities, (47, 48). Notably, some transcription factors coactivated by resulting in distinct destinies following ROS-inducing treatments PGC1a can, in turn, regulate PGC1a, comprising autoregulatory (53, 57). loops that augment target gene transcription (17). The V600E BRAF mutation plays a critical role in melanoma- a genesis by constitutively activating the MAPK signaling pathways PGC1 and Cancer Metabolism (62, 63). Although the BRAF inhibitor, vemurafenib, and the MEK PGC1a has been shown to be a promoter of carcinogenesis in inhibitor, selumetinib, have achieved superior clinical effects to chemical-induced colon and liver carcinoma mouse models (49). treat BRAF V600E–positive individuals, de novo and acquired Figure 1. Regulation mechanisms of PGC1a in cancer. Oncogenes such as MIFT, P53 enhance the transcriptional activity of PGC1a, whereas MYC and HIF suppress it. PGC1a can also be activated by
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