c-Myc activates multiple metabolic networks to generate substrates for cell-cycle entry

197

189

Stimulation of resting CD4 + T lymphocytes leads to rapid proliferation and differentiation into effector (Teff) or inducible regulatory (Treg) subsets with specific functions to promote or suppress immunity. Importantly, Teff and Treg use distinct metabolic programs to support subset specification, survival, and function. Here, we describe that the orphan nuclear receptor estrogen-related receptor-α (ERRα) regulates metabolic pathways critical for Teff. Resting CD4 + T cells expressed low levels of ERRα protein that increased on activation. ERRα deficiency reduced activated T-cell numbers in vivo and cytokine production in vitro but did not seem to modulate immunity through inhibition of activating signals or viability. Rather, ERRα broadly affected metabolic gene expression and glucose metabolism essential for Teff. In particular, up-regulation of Glut1 protein, glucose uptake, and mitochondrial processes were suppressed in activated ERRα −/− T cells and T cells treated with two chemically independent ERRα inhibitors or by shRNAi. Acute ERRα inhibition also blocked T-cell growth and proliferation. This defect appeared as a result of inadequate glucose metabolism, because provision of lipids, but not increased glucose uptake or pyruvate, rescued ATP levels and cell division. Additionally, we have shown that Treg requires lipid oxidation, whereas Teff uses glucose metabolism, and lipid addition selectively restored Tregbut not Teff-generation after acute ERRα inhibition. Furthermore, in vivo inhibition of ERRα reduced T-cell proliferation and Teff generation in both immunization and experimental autoimmune encephalomyelitis models. Thus, ERRα is a selective transcriptional regulator of Teff metabolism that may provide a metabolic means to modulate immunity. glycolysis | fatty acid | oxidative metabolism | mammalian target of rapamycin | AMPK

Section: Resultsmentioning

confidence: 89%

Estrogen-related receptor-α is a metabolic regulator of effector T-cell activation and differentiation

Michalek¹,

Gerriets²,

Nichols³

et al. 2011

197

189

“…In prostate-cancer cells, AR has been shown to regulate metabolic genes involved in glycolysis, PPP, fatty acid, and nucleotide synthesis (11). On the other hand, as one of the most highly amplified oncogenes in many cancers (23), c-Myc emerges as a master regulator of global metabolism, including those regulated by AR, as well as glutamine metabolism and the TCA cycle (14,15). We showed, in both cases, that PCGEM1 associated with the transcription factors, enhanced their transactivation activities, enriched their recruitments to the target promoters, and up-regulated the target genes in all of the pathways described above.…”

Section: Discussionmentioning

confidence: 99%

“…2; summarized in Fig. S3) (14,15). Second, chromatin isolation by RNA purification (ChIRP) analysis showed that PCGEM1 physically associated to a subset of the metabolic gene promoters (Fig.…”

Section: Pcgem1mentioning

confidence: 99%

A long noncoding RNA connects c-Myc to tumor metabolism

Hung

et al. 2014

274

212

Long noncoding RNAs (lncRNAs) have been implicated in a variety of physiological and pathological processes, including cancer. In prostate cancer, prostate cancer gene expression marker 1 (PCGEM1) is an androgen-induced prostate-specific lncRNA whose overexpression is highly associated with prostate tumors. PCGEM1's tumorigenic potential has been recently shown to be in part due to its ability to activate androgen receptor (AR). Here, we report a novel function of PCGEM1 that provides growth advantages for cancer cells by regulating tumor metabolism via c-Myc activation. PCGEM1 promotes glucose uptake for aerobic glycolysis, coupling with the pentose phosphate shunt to facilitate biosynthesis of nucleotide and lipid, and generates NADPH for redox homeostasis. We show that PCGEM1 regulates metabolism at a transcriptional level that affects multiple metabolic pathways, including glucose and glutamine metabolism, the pentose phosphate pathway, nucleotide and fatty acid biosynthesis, and the tricarboxylic acid cycle. The PCGEM1-mediated gene regulation takes place in part through AR activation, but predominantly through c-Myc activation, regardless of hormone or AR status. Significantly, PCGEM1 binds directly to target promoters, physically interacts with c-Myc, promotes chromatin recruitment of c-Myc, and enhances its transactivation activity. We also identified a c-Myc binding domain on PCGEM1 that contributes to the PCGEM1-dependent c-Myc activation and target induction. Together, our data uncover PCGEM1 as a key transcriptional regulator of central metabolic pathways in prostate cancer cells. By being a coactivator for both c-Myc and AR, PCGEM1 reprograms the androgen network and the central metabolism in a tumor-specific way, making it a promising target for therapeutic intervention.L ong noncoding RNAs (lncRNAs) have recently drawn increasing attention as important players in physiological and pathological processes. In cancer, aberrant expression and mutations of lncRNAs can contribute to tumor development and progression by promoting proliferation, invasion, metastasis, and survival (1-3). LncRNAs thus may serve as diagnostic biomarkers and therapeutic targets for cancer. LncRNAs function at several levels of cellular processes, and the majority thus far studied are involved in gene regulation either at the transcriptional or posttranscriptional level (4). At the transcriptional level, lncRNA can serve as a chaperon or scaffold to deliver transcriptional factor to the chromatin site, to modulate the chromatin conformation by recruiting histone-modifying complexes, and to connect distal gene-regulatory elements together to effectively modulate the transcription of the targeted loci (4).Prostate cancer gene expression marker 1 (PCGEM1) is a prostate tissue-specific lncRNA highly associated with prostate cancer (5). Over 80% of patient specimens show elevated levels (5), and the occurrence of PCGEM1 overexpression seems to be significantly higher in African-American patients, whose population has the highest pr...

“…In Burkitt's lymphoma, for example, the c-Myc gene is translocated to one of the Ig loci in virtually all tumors (5,7,8). The MYC oncogene contributes to tumorigenesis by functioning as a global regulator of transcription involving many cellular programs, including cellular growth, metabolism, and lipid synthesis (9,10). MYC induces a global shift in metabolism associated with anaerobic glycolysis, a phenomenon known as the Warburg effect (11).…”

mentioning

confidence: 99%

Alteration of the lipid profile in lymphomas induced by MYC overexpression

Eberlin

Gabay

Fan

et al. 2014

121

103

Overexpression of the v-myc avian myelocytomatosis viral oncogene homolog (MYC) oncogene is one of the most commonly implicated causes of human tumorigenesis. MYC is known to regulate many aspects of cellular biology including glucose and glutamine metabolism. Little is known about the relationship between MYC and the appearance and disappearance of specific lipid species. We use desorption electrospray ionization mass spectrometry imaging (DESI-MSI), statistical analysis, and conditional transgenic animal models and cell samples to investigate changes in lipid profiles in MYC-induced lymphoma. We have detected a lipid signature distinct from that observed in normal tissue and in rat sarcoma-induced lymphoma cells. We found 104 distinct molecular ions that have an altered abundance in MYC lymphoma compared with normal control tissue by statistical analysis with a false discovery rate of less than 5%. Of these, 86 molecular ions were specifically identified as complex phospholipids. To evaluate whether the lipid signature could also be observed in human tissue, we examined 15 human lymphoma samples with varying expression levels of MYC oncoprotein. Distinct lipid profiles in lymphomas with high and low MYC expression were observed, including many of the lipid species identified as significant for MYC-induced animal lymphoma tissue. Our results suggest a relationship between the appearance of specific lipid species and the overexpression of MYC in lymphomas.biostatistics | transgenic models | lipidomics | metabolomics | cancer T he v-myc avian myelocytomatosis viral oncogene homolog (MYC) is commonly overexpressed in human neoplasia (1, 2) and has been strongly associated with the clinical aggressiveness of human cancers (3, 4). MYC is particularly associated with the pathogenesis of hematopoietic tumors such as lymphomas and of epithelial tumors (5, 6). In Burkitt's lymphoma, for example, the c-Myc gene is translocated to one of the Ig loci in virtually all tumors (5,7,8). The MYC oncogene contributes to tumorigenesis by functioning as a global regulator of transcription involving many cellular programs, including cellular growth, metabolism, and lipid synthesis (9, 10). MYC induces a global shift in metabolism associated with anaerobic glycolysis, a phenomenon known as the Warburg effect (11). Several studies have shown a relationship between MYC regulation and metabolism in lymphomas, especially as related to the processes of glycolysis and glutaminolysis (12, 13). Some reports suggest that MYC regulates fatty acid synthesis, specifically palmitate (14); however, little is known about the relationship between MYC expression and the up-regulation or down-regulation of various lipid species in lymphomas.We have generated transgenic mice to conditionally regulate expression of MYC oncogenes alone or in combination with oncogenes such as rat sarcoma (RAS), BCR-ABL, and BCL2 to produce many transgenic models of cancers, including T-cell acute lymphocytic leukemia, acute myeloid leukemia, osteosarcoma, lung adenocarc...