Elsevier

Pharmacology & Therapeutics

Volume 190, October 2018, Pages 187-201
Pharmacology & Therapeutics

From chemo-prevention to epigenetic regulation: The role of isothiocyanates in skin cancer prevention

https://doi.org/10.1016/j.pharmthera.2018.06.001Get rights and content

Abstract

Skin cancer incidence is rapidly growing over the last decades and is generally divided into malignant melanoma and non-melanoma (NMSC) with the latter being subdivided into squamous (SCC) and basal cell carcinoma (BCC). Among them, melanoma is the most aggressive type with high mortality rates. On the other hand, aberrant gene expression is a critical step towards malignant transformation. To this end, epigenetic modifications like changes in DNA methylation patterns and miRNA expression profile as well as histone modifications are all capable of inducing an altered gene expression profile involved in various cellular cascades including cell cycle, proliferation and apoptosis. In general, there is an interest about the beneficiary effect of various phytochemicals in the prevention and treatment of skin malignancies. Among them, glucosinolates are an important type of compounds, abundant in cruciferous vegetables, which are hydrolysed by an endogenous enzyme called myrosinase to a range of bioactive compounds including isothiocyanates (ITCs). These are the major biologically active products capable of mediating the anti-cancer effect of cruciferous vegetables. Their chemo-preventive action is mainly attributed to a plurality of anti-cancer properties including regulation of the epigenetic machinery. Current evidence supports the view that ITCs are potent compounds in interacting with the epigenome in order to restore the normal epigenetic landscape in malignant cells. This review article summarizes the current state of knowledge on the epigenetic modifications that lead to malignant transformation and the role of ITCs with respect to their ability to restore the epigenetic landscape that contributes to skin carcinogenesis.

Introduction

Skin cancer is considered one of the most common types of cancer worldwide with its rates increasing rapidly over the years (Diepgen & Mahler, 2002; Gordon, 2013; Nguyen & Ho, 2002). There are three main types: i) basal and ii) squamous cell cancer (BCC and SCC respectively both of which arise from keratinocytes) as well as iii) melanoma (which originate from melanocytes) (Erb, Ji, Kump, Mielgo, & Wernli, 2008). BCC and SCC together are known as non-melanoma skin cancer (NMSC) with BCC being the most common type accounting for about 80% of the disease’s incidence (Baxter, Patel, & Varma, 2012; Madan, Lear, & Szeimies, 2010). In general, NMSCs have a good prognosis, especially if diagnosed at an early stage in contrast to malignant melanoma which is more aggressive and lethal. Finally, BCCs usually grow locally and rarely metastasize whereas SCCs are more likely to spread to distant areas (Gordon, 2013).

In recent years, a number of genes (involved in several cellular pathways) were shown to be deregulated and thus contribute to the induction, promotion, progression and metastatic stages of the disease (Bosserhoff, 2006; Greinert, 2009; Hocker, Singh, & Tsao, 2008). For instance., BCC is strongly associated with the deregulation of the sonic hedgehog signalling pathway (Athar, Li, Kim, Spiegelman, & Bickers, 2014) whereas mutations in the p53-regulated pathways are of particular importance for the initiation of SCC (Emmert, Schön, & Haenssle, 2014). Other genes may also contribute in SCC development including RAS and pl6INK4a although mutations in these genes are observed at a lower frequency than p53 (Emmert et al., 2014; Xie, 2008). In malignant melanoma, various signalling pathways have been shown to be deregulated with the most important one being the RAS-ERK (Dahl & Guldberg, 2007; Ko & Fisher, 2011; Shtivelman et al., 2014). In particular, mutations in the BRAF gene are the most common lesions among melanoma patients (Shtivelman et al., 2014).

On the other hand, epigenetic modifications can contribute to malignant transformation by means of altering gene expression responsible for abnormal cell proliferation (Sigalotti et al., 2010). Because epigenetic modifications are reversible (in contrast to genetic mutations) there is a growing interest in identifying agents with the potential to interact with the cancer epigenome and thus restore its “normal” state. In this context, various dietary phytochemicals have been shown to exhibit a plurality of biological properties (e.g. anti-inflammatory, anti-proliferative, anti-mutagenic, anti-oxidant, anti-cancer, etc.) in addition to their capacity of regulating gene expression by means of modulating the epigenetic response (Fitsiou., Mitropoulou, et al., 2016; Fitsiou, Anestopoulos, et al., 2016; Fitsiou et al., 2018; Issa, Volate, & Wargovich, 2006; Johnson, 2007; Li et al., 2014; Li et al., 2016; Nohynek et al., 2006; Rupasinghe, Sekhon-Loodu, Mantso, & Panayiotidis, 2016; Spyridopoulou et al., 2017; Supic, Jagodic, & Magic, 2013; Ziech et al., 2012). Among the various types of phytochemicals, isothiocyanates (ITCs) are found abundant in cruciferous vegetables of the Brassicaceae family (e.g. cauliflower, cabbage, broccoli, Brussels sprouts, etc.) and have been shown to contribute to cancer prevention through a wide range of mechanisms including modulation of the epigenetic response (Abdull, Ahmad, & Noor, 2013; Fahey, Zhang, & Talalay, 1997; Li et al., 2016; Murillo & Mehta, 2001; Sahu & Srivastava, 2009; Talalay & Zhang, 1996; Zhang & Talalay, 1994; Zhang, Talalay, Cho, & Posner, 1992).

In this review article, we discuss the current state of knowledge regarding the epigenetic landscape of skin cancer and the importance of such epigenetic alterations in the initiation and progression of the disease. Finally, we discuss the underlying mechanism(s) by which ITCs interact with the skin cancer epigenome in order to restore its normal function.

Section snippets

Risk factors

Skin cancer incidence is multifactorial and its development is based on innate predisposition, inheritable traits, environmental agents and geographical origin all of which play an important role in the disease susceptibility (Chang, Feng, Gao, & Gao, 2010; Martin-Gorgojo et al., 2017; Moan, Grigalavicius, Baturaite, Dahlback, & Juzeniene, 2015; Narayanan, Saladi, & Fox, 2010). Briefly, ultraviolet radiation (UVR) is considered as the main cause of skin cancer formation and increases the risk

Myrosinase - glucosinolate system

Cruciferous vegetables are rich sources of glucosinolates (GLs) which are hydrolysed by myrosinase (Andréasson & Jørgensen, 2003). Inside the plant, the enzyme is physically isolated from their substrates thus allowing the degradation of GLs only when the plant is under stress conditions like pathogen attack or tissue disruption (Andréasson, Jørgensen, Höglund, Rask, & Meijer, 2001; del Carmen Martinez-Ballesta & Carvajal, 2015; Koroleva et al., 2000). Chewing or cutting leads to the release of

Overview of epigenetic mechanisms and their role in cancer development

The term “epigenetics” refers to heritable and reversible changes in gene expression patterns that are independent from the DNA sequence itself (Probst, Dunleavy, & Almouzni, 2009). These changes are established early in life and contribute to the differentiation of cells via modifications in DNA and histone proteins (Margueron & Reinberg, 2010). In addition, the epigenetic machinery also plays an important role in many physiological processes including genomic imprinting (Ferguson-Smith &

Concluding remarks

ITCs are an important class of bio-active dietary agents considered to be of great value in various industries (e.g. food, nutraceutical, cosmetic, pharmaceutical, etc.) due to their wide range of biological properties (e.g. anti-bacterial, anti-inflammatory, anti-aging, anti-cancer, etc.). In the context of their anti-cancer activity, ITCs have been shown to interfere with many cellular pathways (e.g. growth, proliferation, apoptosis, etc.) which are usually found to be deregulated in cancer

Conflict of interest statement

The authors declare that there is no conflict of interest.

Acknowledgements

This work was supported by start-up funds (Prof. Panayiotidis) including a PhD studentship (Mrs. Mitsiogianni) provided by the Multi-Disciplinary Research Theme (MDRT) in “Bio-economy” of Northumbria University (UNN).

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