ABSTRACT
Cancer is a disease characterized by unrestrained cellular proliferation. In order to sustain growth, cancer cells undergo a complex metabolic rearrangement characterized by changes in metabolic pathways involved in energy production and biosynthetic processes. The relevance of the metabolic transformation of cancer cells has been recently included in the updated version of the review "Hallmarks of Cancer", where dysregulation of cellular metabolism was included as an emerging hallmark. While several lines of evidence suggest that metabolic rewiring is orchestrated by the concerted action of oncogenes and tumor suppressor genes, in some circumstances altered metabolism can play a primary role in oncogenesis. Recently, mutations of cytosolic and mitochondrial enzymes involved in key metabolic pathways have been associated with hereditary and sporadic forms of cancer. Together, these results demonstrate that aberrant metabolism, once seen just as an epiphenomenon of oncogenic reprogramming, plays a key role in oncogenesis with the power to control both genetic and epigenetic events in cells. In this review, we discuss the relationship between metabolism and cancer, as part of a larger effort to identify a broad-spectrum of therapeutic approaches. We focus on major alterations in nutrient metabolism and the emerging link between metabolism and epigenetics. Finally, we discuss potential strategies to manipulate metabolism in cancer and tradeoffs that should be considered. More research on the suite of metabolic alterations in cancer holds the potential to discover novel approaches to treat it.
Subject(s)
Carcinogenesis/metabolism , Mitochondria/metabolism , Neoplasms/metabolism , Carcinogenesis/genetics , Cell Proliferation/genetics , Cell Transformation, Neoplastic/genetics , Energy Metabolism/genetics , Epigenesis, Genetic , Humans , Metabolic Networks and Pathways/genetics , Mitochondria/genetics , Mitochondria/pathology , Neoplasms/genetics , Neoplasms/pathologyABSTRACT
Many diseases, such as diabetes, autoimmune diseases, cancer, and neurological disorders, are caused by a dysregulation of a complex interplay of genes. Genome-wide association studies have identified thousands of disease-linked polymorphisms in the human population. However, detailing the causative gene expression or functional changes underlying those associations has been elusive in many cases. Functional genomics is an emerging field of research that aims to deconvolute the link between genotype and phenotype by making use of large -omic data sets and next-generation gene and epigenome editing tools to perturb genes of interest. Here we review how functional genomic tools can be used to better understand the biological interplay between genes, improve disease modeling, and identify novel drug targets. Incorporation of functional genomic capabilities into conventional drug development pipelines is predicted to expedite the development of first-in-class therapeutics.
Subject(s)
Drug Discovery/trends , Genetic Predisposition to Disease , Genome, Human/genetics , Genomics/trends , CRISPR-Cas Systems/genetics , Epigenome/genetics , Gene Editing , Genome-Wide Association Study , Genotype , Humans , Phenotype , RNA, Small Interfering/geneticsABSTRACT
Tumors display profound changes in cellular metabolism, yet how these changes aid the development and growth of tumors is not fully understood. Here we use a multi-omic approach to examine liver carcinogenesis and regeneration, and find that progressive loss of branched-chain amino acid (BCAA) catabolism promotes tumor development and growth. In human hepatocellular carcinomas and animal models of liver cancer, suppression of BCAA catabolic enzyme expression led to BCAA accumulation in tumors, though this was not observed in regenerating liver tissues. The degree of enzyme suppression strongly correlated with tumor aggressiveness, and was an independent predictor of clinical outcome. Moreover, modulating BCAA accumulation regulated cancer cell proliferation in vitro, and tumor burden and overall survival in vivo. Dietary BCAA intake in humans also correlated with cancer mortality risk. In summary, loss of BCAA catabolism in tumors confers functional advantages, which could be exploited by therapeutic interventions in certain cancers.
Subject(s)
Amino Acids, Branched-Chain/metabolism , Carcinogenesis/metabolism , Carcinoma, Hepatocellular/metabolism , Disease Progression , Down-Regulation , Liver Neoplasms/metabolism , Mechanistic Target of Rapamycin Complex 1/metabolism , Aged , Aged, 80 and over , Amino Acids, Branched-Chain/administration & dosage , Amino Acids, Branched-Chain/pharmacology , Animals , Carcinogenesis/drug effects , Carcinoma, Hepatocellular/pathology , Cell Proliferation/drug effects , Cohort Studies , Disease Models, Animal , Female , Hep G2 Cells , Humans , Liver Neoplasms/pathology , Male , Mice , Mice, Inbred C57BL , Middle Aged , Rats , Rats, Inbred ACIABSTRACT
Cells integrate nutrient sensing and metabolism to coordinate proper cellular responses to a particular nutrient source. For example, glucose drives a gene expression program characterized by activating genes involved in its metabolism, in part by increasing glucose-derived histone acetylation. Here, we find that lipid-derived acetyl-CoA is a major source of carbon for histone acetylation. Using 13C-carbon tracing combined with acetyl-proteomics, we show that up to 90% of acetylation on certain histone lysines can be derived from fatty acid carbon, even in the presence of excess glucose. By repressing both glucose and glutamine metabolism, fatty acid oxidation reprograms cellular metabolism, leading to increased lipid-derived acetyl-CoA. Gene expression profiling of octanoate-treated hepatocytes shows a pattern of upregulated lipid metabolic genes, demonstrating a specific transcriptional response to lipid. These studies expand the landscape of nutrient sensing and uncover how lipids and metabolism are integrated by epigenetic events that control gene expression.
Subject(s)
Caprylates/pharmacology , Carbon/pharmacology , Histones/metabolism , Lipid Metabolism/drug effects , Acetyl Coenzyme A/metabolism , Acetylation/drug effects , Amino Acid Sequence , Animals , Cell Line, Tumor , Gene Expression Profiling , Gene Expression Regulation/drug effects , Histone Deacetylase Inhibitors/pharmacology , Histones/chemistry , Humans , Lipid Metabolism/genetics , Mice , Oxidation-ReductionABSTRACT
The mitochondrial sirtuin SIRT3 is a protein deacylase that influences almost every major aspect of mitochondrial biology, including nutrient oxidation, ATP generation, reactive oxygen species (ROS) detoxification, mitochondrial dynamics, and the mitochondrial unfolded protein response (UPR). Interestingly, mice lacking SIRT3 (SIRT3KO), either spontaneously or when crossed with mouse models of disease, develop several diseases of aging at an accelerated pace, such as cancer, metabolic syndrome, cardiovascular disease, and neurodegenerative diseases, and, thus, might be a valuable model of accelerated aging. In this review, we discuss functions of SIRT3 in pathways involved in diseases of aging and how the lack of SIRT3 might accelerate the aging process. We also suggest that further studies on SIRT3 will help uncover important new pathways driving the aging process.
Subject(s)
Aging/genetics , Disease/genetics , Sirtuin 3/genetics , Animals , Humans , Longevity , MiceABSTRACT
The sirtuins are a family of highly conserved NAD(+)-dependent lysine deacylases with important roles in metabolic regulation. Of the seven mammalian sirtuins, three localize to the mitochondria: SIRT3, SIRT4, and SIRT5. Mitochondrial sirtuins are crucial regulators of the metabolic network that controls energy homeostasis and impacts cancer, obesity, diabetes, mitochondrial diseases, metabolic disorders, and many other human diseases of aging. To best study the mitochondrial function of the sirtuins, we have employed an oxygen flux analyzer as a tool to track and record the extracellular oxygen consumption rate and acidification rate that reflects mitochondrial respiration and glycolysis, respectfully. Here we described the methods using this assay to study the substrate utilization and mitochondrial function in a human hepatocellular carcinoma cell line, Huh7. Additionally, we have generated a stable SIRT4 knocked-down Huh7 cell line. With this cell line, we evaluated how the absence of SIRT4 affects mitochondrial function, glucose utilization, glutamine oxidation, and fatty acid oxidation in these cells.
Subject(s)
Carcinoma, Hepatocellular/metabolism , Fatty Acids/chemistry , Glutamine/chemistry , Liver Neoplasms/metabolism , Mitochondria/metabolism , Mitochondrial Proteins/metabolism , Oxygen/metabolism , Sirtuins/metabolism , Fatty Acids/metabolism , Glucose/metabolism , Glutamine/metabolism , Homeostasis , Humans , Immunoblotting , Mitochondrial Proteins/antagonists & inhibitors , Mitochondrial Proteins/genetics , Oxidation-Reduction , Oxygen Consumption , RNA, Small Interfering/genetics , Sirtuins/antagonists & inhibitors , Sirtuins/genetics , Tumor Cells, CulturedABSTRACT
The forkhead transcription factor FOXP3 is necessary for induction of regulatory T lymphocytes (Tregs) and their immunosuppressive function. We have previously demonstrated that targeting Tregs by vaccination of mice with murine FOXP3 mRNA-transfected dendritic cells (DCs) elicits FOXP3-specific T cell responses and enhances tumor immunity. It is clear that FOXP3 expression is not restricted to T-cell lineage and herein, using RT-PCR, flow cytometry, and western immunoblot we demonstrate for the first time that FOXP3 is expressed in inflammatory breast cancer (IBC) cells, SUM149 (triple negative, ErbB1-activated) and SUM190 (ErbB2-overexpressing). Importantly, FOXP3-specific T cells generated in vitro using human FOXP3 RNA-transfected DCs as stimulators efficiently lyse SUM149 cells. Interestingly, an isogenic model (rSUM149) derived from SUM149 with an enhanced anti-apoptotic phenotype was resistant to FOXP3-specific T cell mediated lysis. The MHC class I cellular processing mechanism was intact in both cell lines at the protein and transcription levels suggesting that the resistance to cytolysis by rSUM149 cells was not related to MHC class I expression or to the MHC class I antigen processing machinery in these cells. Our data suggest that FOXP3 may be an effective tumor target in IBC cells however increased anti-apoptotic signaling can lead to immune evasion.