From chemo-prevention to epigenetic regulation: The role of isothiocyanates in skin cancer prevention
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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2023, Biochimica et Biophysica Acta - Molecular Basis of DiseaseTargeting the epigenome in malignant melanoma: Facts, challenges and therapeutic promises
2022, Pharmacology and TherapeuticsCitation Excerpt :Malignant melanoma, as in most cancer types, displays an aberrant profile of DNA methylation. When hypermethylation of various tumor suppressor genes occurs, it results in their expression levels being either completely silenced and/or significantly reduced (Micevic, Theodosakis, & Bosenberg, 2017; Mitsiogianni et al., 2018; Rothhammer & Bosserhoff, 2007; van den Hurk et al., 2012). Specifically various studies have reported hypermethylation of different tumor suppressor genes such as APC (de Unamuno Bustos et al., 2018; Liu, Ren, Howell, Fodstad, & Riker, 2008; Worm, Christensen, Grønbæk, Tulchinsky, & Guldberg, 2004), CDKN1B/2A (de Unamuno Bustos et al., 2018; Gonzalgo et al., 1997; Liu et al., 2008; Schinke et al., 2010; Straume, Smeds, Kumar, Hemminki, & Akslen, 2002), DAPK1 (Hoon et al., 2004a; Liu et al., 2008), E-cadherin (Furuta et al., 2006; Liu et al., 2008; Tellez et al., 2009; Venza et al., 2016), MGMT (Hoon et al., 2004; Komine et al., 2003; Liu et al., 2008; Marini et al., 2006), RASSF1A/6/10 (de Unamuno Bustos et al., 2018; Furuta et al., 2004; Helmbold et al., 2012; Hoon et al., 2004; Marini et al., 2006; McKenna & García-Gutiérrez, 2021; Mezzanotte et al., 2014; Tanemura et al., 2009; Yi et al., 2011), PTEN (de Unamuno Bustos et al., 2018; Lahtz, Stranzenbach, Fiedler, Helmbold, & Dammann, 2010; Mirmohammadsadegh et al., 2006) among others, implicated in important cellular processes including apoptosis, cell cycle regulation, DNA repair as well as invasion and metastasis.
Isothiocyanate Iberin inhibits cell proliferation and induces cell apoptosis in the progression of ovarian cancer by mediating ROS accumulation and GPX1 expression
2021, Biomedicine and PharmacotherapyCitation Excerpt :Iberin belongs to the family of isothiocyanates (ITCs) which are group of bioactive compounds obtained from cruciferous vegetables [18]. ITCs could repress tumor development by inducing cell cycle arrest, promoting cell apoptosis and inhibiting cell growth in tumors [19–21]. Consistent with these findings, Iberin is validated to inhibit cell proliferation and induced cell apoptotic death of OC cells in this study.
Cruciferous vegetable consumption and pancreatic cancer: A case-control study
2021, Cancer EpidemiologyCitation Excerpt :Phytochemicals found in cruciferous vegetables may play a role in pancreatic cancer prevention. Glucosinolate, in particular, is a precursor of dietary ITCs, which have been shown to protect against chemically induced tumors, interacting with the epigenome to restore the normal landscape in malignant cells, and regulating epigenetic mechanisms [34]. Animal studies have shown that ITC may help decrease the development of pancreatic cancer [6,26,27,35,36].
Nutrients and phytonutrients as promising epigenetic nutraceuticals
2021, Medical EpigeneticsSulforaphane in broccoli-based matrices: Effects of heat treatment and addition of oil
2020, LWTCitation Excerpt :In particular, the health benefits have been associated with sulforaphane (1-isothiocyanato-4-methylsulfinylbutane), the isothiocyanate formed by the action of endogenous myrosinase on the glucosinolate, glucoraphanin. Sulforaphane has been linked with reducing cancer risk (Clarke, Dashwood, & Ho, 2008; Jeffery & Araya, 2009; Mitsiogianni et al., 2018), improving cardiovascular health, and having beneficial effects for neurological conditions, autism and osteoporosis (Vanduchova, Anzenbacher, & Anzenbacherova, 2019). Although there are limited human studies, it has been suggested as a therapeutic for the treatment of diabetes (Axelsson et al., 2017; Yamagishi & Matsui, 2016), malignant brain tumours (Sita, Hrelia, Graziosi, & Morroni, 2018), osteoarthritis (Davidson et al., 2016) and bladder cancer (Abbaoui, Lucas, Riedl, Clinton, & Mortazavi, 2018), and for the prevention of skin cancer (Mitsiogianni et al., 2018).