Elsevier

Seminars in Cancer Biology

Volume 51, August 2018, Pages 59-67
Seminars in Cancer Biology

Review
Vitamin C – A new player in regulation of the cancer epigenome

https://doi.org/10.1016/j.semcancer.2017.11.001Get rights and content

Abstract

Over the past few years it has become clear that vitamin C, as a provider of reduced iron, is an essential factor for the function of epigenetic regulators that initiate the demethylation of DNA and histones. Vitamin C deficiency is rare in the general population, but is frequently observed in patients with cancer. Genes encoding epigenetic regulators are often mutated in cancer, underscoring their central roles in carcinogenesis. In hematological cancers, such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), drugs that reverse epigenetic aberrations are now the standard of care. Recent in vitro studies suggest that vitamin C at physiological concentrations, combined with hypomethylating agents may act synergistically to cause DNA demethylation through active and passive mechanisms, respectively. Additionally, several recent studies have renewed interest in the use of pharmacological doses of vitamin C injected intravenously to selectively kill tumor cells. This review will focus on the potential of vitamin C to optimize the outcome of epigenetic therapy in cancer patients and alternatively to act as a therapeutic at high doses.

Introduction

Vitamin C enhances the activity of multiple enzymes, and it has diverse functions in almost all tissues of the body. Unlike plants and most animals, humans are unable to synthesize vitamin C from glucose due to the lack of the enzyme l-gulonolactone oxidase, so vitamin C must be provided through the diet.

Vitamin C was discovered in the 1930s by Nobel Prize winner Albert Szent-Györgyi as the necessary micronutrient for the prevention of scurvy, and it was named ascorbic acid from Latin, meaning “without scurvy” [1]. The positive effects of vitamin C in both the prevention and treatment of various diseases were popularized with little objective evidence by Linus Pauling. By the 1950s, vitamin C deficiency was proposed to play an important role in carcinogenesis [2]. In early studies, vitamin C alone was suggested as a potential treatment for cancer. Since then, several studies have examined the effects of vitamin C in combination with chemotherapy, the rationale being that vitamin C may enhance the effects of chemotherapy, reduce the side effects, or both [3], [4].

Until recently, most of the interest in vitamin C function focused on its demonstrated ability to serve as a co-factor for prolyl hydroxylase which converts proline residues in type 1 collagen to hydroxyproline. Interestingly, most tissue culture medium does not contain the vitamin which must be added daily to ensure the deposition of cross-linked collagen on to culture dishes [5]. That vitamin C might have functions in addition to this, was suggested by early experiments demonstrating that it could completely block oncogenic transformation induced by chemical carcinogens [6]. Reprogramming of cells is strongly enhanced by vitamin C, which was shown to be associated with decreased levels of DNA cytosine methylation [7], [8], [9], [10]. These findings raise concerns about the use of unsupplemented media in vitro since the results might be strongly influenced by the lack of efficient demethylation in chromatin.

More recently, functional studies have shed light on the potential mechanisms by which vitamin C exerts its effects in cancer cells. At physiological doses, vitamin C acts as an antioxidant (Fig. 1). However, vitamin C at pharmacological doses (>100 μM) has been found to promote the formation of large amounts of reactive oxygen species (ROS) and thus cause DNA damage [11]. A recent study showed that high dose vitamin C selectively kills colon cancer cells carrying KRAS or BRAF mutations by elevating the level of endogenous ROS, which inhibits GAPDH and leads to energy depletion and cell death [12].

A different view of the potential action of vitamin C in cancer came from the discovery of its importance for the activation of the ten-eleven translocation (TET) and Jumonji dioxygenases that are involved in active demethylation of DNA and histones, respectively [13], [14]. Aberrant DNA and histone methylation are hallmarks of all cancers and may result from altered expression of, or point mutations in, the genes encoding these regulatory enzymes. Given that the TET and Jumonji dioxygenases depend on vitamin C, suboptimal levels of the vitamin may well alter chromatin homeostasis in both healthy and cancerous cells.

Recent in vitro studies from our group and others [15], [16] have shown that vitamin C at physiological levels potentiates the effects of DNA methyltransferase inhibitors (DNMTis; also known as hypomethylating agents), which are routinely used in the treatment of hematological cancers. The combination treatment caused significantly increased growth inhibition probably by up-regulation of human endogenous retroviruses resulting in a state of “viral mimicry” and activation of the viral defence pathway [15], [17], [18], and also in the induction of cryptic transcriptional start sites [19].

Here, we provide an overview of the role of vitamin C as an essential factor for epigenetic regulation and its potential to optimize the outcome of epigenetic therapy in cancer patients.

Section snippets

Vitamin C – A crucial multifunctional molecule

The recommended daily intake of vitamin C (75–90 mg/d) [20] should easily be met by consuming a varied diet that includes fruit and vegetables, and an oral intake of merely 10 mg/d is enough to prevent scurvy. However, cancer patients often have a low amount of vitamin C in the blood and therefore supplementation may be necessary [21], [22], [23]. In line with this, a higher intake of vitamin C (120 mg/d) has been recommended for elderly (≥75 years) based on considerations related to cancer risk,

Vitamin C in epigenetic control

A relatively newly discovered and somewhat unexpected role for vitamin C is in the function of the TET and Jumonji enzymes, and thus it may be essential for epigenetic regulation. These sets of enzymes both belong to the Fe(II)- and α-ketoglutarate-dependent dioxygenase superfamily.

Vitamin C deficiency in cancer patients

Individuals with cancer have significantly lower plasma vitamin C levels than healthy individuals [15], [21], [22], [23], [56]. Plasma vitamin C may be even lower in patients with aggressive cancers [22], including patients undergoing allogeneic hematopoietic stem cell transplantation [57]. Cancer-induced oxidative stress and ROS formation is one explanation for such a deficiency (Fig. 2). The release of free radicals from an advancing cancer likely results in an increased consumption of

Conclusion

Cancer is driven by epigenetic alterations in close synergy with genetic changes. Epigenetic therapies are the standard of care for some hematological cancers, but many patients show primary resistance and there is need for improvement. Vitamin C assists the TET and JHDM enzymes that are responsible for the removal of methyl groups for DNA and histones. Vitamin C deficiency in cancer patients is frequent, and there may be an increased need for vitamin C in cancer patients and individuals who

Acknowledgments

Research funding provided by the Danish Cancer Society, Rigshospitalets Research Foundation, Lundbeck Foundation, Novo Nordisk Foundation, the National Institute of Health (grant R35CA209858 to P.A.J.) and Van Andel Research Institute through the Van Andel Research Institute − Stand Up To Cancer Epigenetics Dream Team. Stand Up To Cancer is a program of the Entertainment Industry Foundation, administered by the American Association for Cancer Research.

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