Review ArticleRedox regulation of the epigenetic landscape in Cancer: A role for metabolic reprogramming in remodeling the epigenome
Graphical abstract
Highlights
► Cancer is a disease associated with changes in metabolism, redox, and gene expression. ► The mechanisms leading to epigenetic alterations during carcinogenesis are unknown. ► Epigenetic disruption of cancer genes is linked to aberrant mitochondrial metabolism. ► Metabolic redox changes alter cofactor availability to enzymes that alter chromatin. ► Aberrant metabolic and redox changes cause epigenetic instability in cancer.
Introduction
Cancer is a constellation of individual diseases arising from various tissues and cell types of origin. In addition to their fundamental irreversible genetic bases of origin (initiation), diverse types of cancer share certain other fundamental underlying similarities including aberrant gene expression, an atypical redox state, and fundamental defect in metabolism often called the Warburg effect. Characterizing malignant phenotypes has proven to be a relatively straightforward process; however, elucidating factors causal in its manifestation has proven more difficult. Such a gap in knowledge left us to ponder and speculate about mechanisms responsible for forming and sculpting malignancies and about how a single or finite number of genotypes, through adaptation and selection by the tumor microenvironment, can give rise to numerous different phenotypes in a relatively short period of time. The discovery by Bishop and Varmus that human genomic DNA contains sequences homologous to transforming retroviral oncogenes led to the formation of the genetic theory of cancer in the 1980 s. Since then, numerous studies have examined genetic alterations in cancer and genomic instability, thus firmly cementing the concepts of activating driver mutations in genes that normally stimulate proliferation (oncogenes) and/or inactivating mutations in genes that inhibit proliferation (tumor suppressor genes). Despite these analyses, and although much insight has been gained from these studies, the mutation frequency of normal cells is paradoxically low, suggesting cancer should rarely develop in the first place [1]. Consistent with these views are the numerous inheritable disorders that predispose individuals to developing certain malignancies [2].
Before the genetic theory of cancer that has predominated over the past 4 decades, a prevailing theory of the development and progression of cancer was the metabolic theory of cancer. Over 70 years ago Otto Warburg observed increased glucose metabolism in tumor cells, suggesting a that metabolic defect may be causal in the development of cancer [3]. This increased need for glucose by cancer cells did not seem to be necessary for them to make ATP because tumor cells could make sufficient ATP by respiration but still displayed increased glucose demand. In contrast, glucose-derived carbon is probably used for the increased biosynthetic demand of rapidly growing cell populations as well for providing reducing equivalents in the form of NADH generated during glycolysis. The NADH and pyruvate resulting from glycolysis are both potent protectors against the increased oxidative stress associated with tumor cells. An extension of these concepts is the free radical theory of cancer rendered by Oberley and Buettner in the late 1970 s [4]. They suggested that free radicals, produced by aberrant reduction of oxygen, initiate cancer (mutationally as by DNA oxidation to 8-OHdG) and additionally provide the momentum for proliferation (promotion) to drive disease progression to malignancy. More recently the epigenetic origins of cancer initiation have been suggested as a further mechanism to fashion the malignant phenotype [5]. In addition, the mounting discoveries of mutations in tricarboxylic acid (TCA) cycle genes that act in interesting ways to perturb epigenetics through central metabolism portend a paradigm shift in the thinking regarding the role of how metabolism drives oncogenic alterations in gene expression during cancer progression.
Epigenetic processes are involved in many facets of molecular and cell biology including regulation of transcription, the cell cycle, DNA repair, and DNA replication. Involvement in these processes puts epigenetics in direct control of Hanahan and Weinberg’s phenotypes of cancer: limitless replicative potential, self-sufficiency in growth signals, insensitivity to anti-growth signals, ability to evade apoptosis, increased tissue invasion, and sustained angiogenesis [6]. The dossier of cancer epigenetics includes detailed information on its ability to create each of these characteristics by influencing transcription, the cell cycle, DNA repair, and DNA replication (for reviews on these topics see [7], [8], [9]). Cancer can be conceptualized as a disease originating via the clonal expansion of a single transformed cell (clonogen). As the clonogenic progenitor divides, something intrinsic to the progenitor’s biology allows it to incur additional epigenetic and genetic alterations. The accumulation of these genetic and epigenetic flaws over several generations creates the malignant phenotype. This epigenetic basis for cancer is summed up by the epigenetic progenitor origin of human cancer suggested by Feinberg, Ohlsson, and Henikoff [5]. Their model aptly suggests that the stochastic epigenetic inactivation of key genes in clonogens gives rise to many malignancies; however, it does not suggest what flaw in the progenitor’s biology is responsible for creating its founding epigenetic alterations. Extending this model to provide a means to generate founding epigenetic alterations in a clonogenic progenitor cell would lend further credence this model. Recently the discovery and characterization of the enzymes involved in creating, maintaining, and removing epigenetic marks has become an area of interest. This has led to a wealth of information regarding these enzymes’ biochemistry. We propose that founding epigenetic events in cancer are forged by changes in redox biology and metabolism. We have previously explored the link between epigenetic processes, cancer, development, and disease [10], [11], [12]. Here, we seek to couple the recent burst of knowledge regarding the biochemistry of epigenetic enzymes with cancer’s altered gene expression, atypical redox state, and defective metabolism.
Section snippets
Overview
The basic sources from which cells derive energy include glucose, fatty acids, ketone bodies, amino acids, and lactate. Tissues do exhibit specificity with respect to the fuel source(s) they burn and create. Eukaryotes can interchange one energy source for another in various anabolic and catabolic pathways. This is dictated by the enzymatic pathways present within a cell or via regulatory mechanisms such as substrate availability/inhibition, posttranslational modification, and the ability to
The metabolic connection to histone acetylation
Numerous studies have demonstrated that histone acetylation is altered in cancer. The levels of acetylation at numerous histone lysines are altered in cancer and may correlate with disease progression [21], [22], [23]. Indeed, although the expression of many HATs and HDACs is altered in cancer, their activity is still dependent upon the availability of their cofactors [24], [25], [26], [27]. A stunning association exists between protein acetylation and glycolysis. The abnormally high levels of
Demethylation of 5-methylcytosine and histones
Until the recent discovery of enzymes that remove methyl groups from DNA and histones, methylation was believed to be a static epigenetic mark. Two families of histone demethylases are known to exist: lysine-specific demethylase 1 (LSD1) and the JmjC family of histone demethylases. LSD1 uses its histone demethylase activity to function both as a transcriptional repressor and as an activator, depending on the context in which it is functioning [75]. The active site of LSD1 has flavin-dependent
Anaplerotic sources of carbon
From our discussion above it is clear that the channel by which carbon flows through metabolism is dramatically altered in cancer. These cancer-associated metabolic changes have the potential to influence DNA and histone methylation in a manner similar to acetylation. Warburg’s initial explanation for the effect bearing his name was that the mitochondria of tumor cells must be inactive. Today, several fundamental defects in mitochondrial function have been described in cancer that influence the
Influence of oxidation on epigenetics
The pro-oxidant state of cancer can directly influence epigenetic processes. This can be accomplished through the oxidation of DNA and oxidizing histones. The formation of 8-oxoguanine (8-OG) is a paradigm of oxidative damage to DNA in free radical biology. 8-OG is highly mutagenic because it can be perceived as adenine or guanine by DNA repair machinery. However, its presence is equally likely to induced epigenetic changes if the oxidation event occurs at a CpG dinucleotide. The presence of
Summary
Characterization of the malignant phenotype has yielded an abundance of information about cancer. However, even with this wealth of information we are still left speculating as to what mechanisms manifest its existence. Cancer requires extreme defects in cellular metabolism to produce its energy and support its increased rate of replication. Could these universal defects in metabolism be the impetus for cancer’s development? Phenotype can be defined as the expression of a cell’s genotype in
Acknowledgements
The authors thank Larry Oberley for his vision and omnipresent guidance in this field of inquiry. Research leading to the concepts and ideas in this work were supported by NIH grants R01 CA073612 and R01 CA115438. We also wish to acknowledge support from a Kaiser Permanente Southern California Regional Research Committee grant which is partially supported by the Southern California Permanente Medical Group Research and Evaluation Department and Direct Community Benefit Investment funds.
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