ReviewTargeting emerging cancer hallmarks by transition metal complexes: Epigenetic reprogramming and epitherapies. Part II
Graphical abstract
Introduction
In 2000, Weinberg and Hanahan organized the evidence of cancer development and summarised the common capabilities shared by most human tumors into six essential alterations that are required by cells to acquire malignant phenotype [1]. These six essential alterations, including self-sufficiency in growth signals, insensitivity to anti-growth signals, tissue invasion and metastasis, limitless replicative potential, sustained angiogenesis and evading apoptosis were termed the “Hallmarks of Cancer” (Fig. 1). In 2011, two new hallmarks – deregulating cellular energetics and avoiding immune destruction, as well as two enabling characteristics – genome instability and tumor-promoting inflammation, were further included into the classification (Fig. 1) [2]. Recently, Hanahan further expanded the existing classification by the addition of four new hallmarks and enabling characteristics, including unlocking phenotypic plasticity, nonmutational epigenetic reprogramming, polymorphic microbiomes and senescent cells (Fig. 1) [3]. The newly added hallmarks and enabling characteristics revealed the emerging role of tumor microenvironment (TME) in cancer pathogenesis. Since TME was characterized by altered metal homeostasis, we hypothesized that rationally-designed transition metal complexes might interfere with the function of various TME components and might represent a promising therapeutic option for treating cancers. In Part I of this review, the therapeutic strategies developed for targeting phenotypic plasticity and cancer microbiome with transition metal were summarised and extensively covered [4]. Herein, we will focus on the use of transition metals as therapeutic drugs to treat malignancies arising from epigenetic dysregulation and compare the therapeutic approaches of transition metal complexes over existing treatment options.
The term “epigenetics” was originally proposed by C. H. Waddington in 1942 from the perspective of embryology [5] and literally means “in addition to or beyond genetics” [6]. Thus, epigenetics encompasses any process that results in a change in genes without altering DNA and can serve as a link between genotype and phenotype [7]. Epigenetic processes influence the implementation of the genetic code throughout the life of the cell and are affected by a wide range of factors, both physiological (e.g. embryological, aging) [8] and pathological (e.g. cancer) [9], [10]. Embryological epigenetic rearrangements have a greater impact on the implementation of the genetic program [11] because they occur in embryonic stem cells and can be transferred to more differentiated cell populations, in contrast to the changes that occur in adult cells [12], [13], [14]. However, pathological factors, such as the process of cancer development, were also shown to significantly influence epigenetic regulation of cells [15], [16], [17].
The analysis of differential epigenetic mechanisms in healthy and cancer patients revealed the potential role of epigenetics as a therapeutic target for cancer. Therapeutic modulation of epigenetic mechanisms governing cancer cells might be used to enhance the cytotoxicity of chemotherapeutic and targeted treatment regimens. On the other hand, regulation of epigenetic mechanisms in healthy cells might be useful for enhancing their defense activity. According to the current classification of major epigenetic mechanisms, they can be divided into three groups: 1) writers, which are responsible for modifications of DNA and histones; 2) readers, which recognize and elucidate these modifications, and 3) erasers, which are the proteins that can remove these modifications [18], [19]. This review will summarize the role of each group of epigenetic modulators in cancer development and describe the existing epitherapies, which are either approved by the FDA (Table 1) or currently investigated in clinical trials (Table 2). Subsequently, we will summarize transition metal complexes that have been developed to interfere with different epigenetic modulators involved in the nonmutational epigenetic reprogramming.
Section snippets
Epigenetic writers
Writers can modify the structure of DNA and histone proteins by attaching various chemical groups. These modifications include methylation [20], acetylation [21], phosphorylation [22], ubiquitylation [23], SUMOylation [24] etc., with methylation and acetylation being the most common and consequential. Methylation involves the addition of a methyl group to either DNA or histone proteins, while acetylation involves the addition of an acetyl group to histone proteins, but not DNA [20], [25], [26].
Epigenetic readers
Epigenetic readers are cellular proteins that recognize the epigenetic modifications carried out by writers in order to mediate their effects. These reader proteins contain specific domains that recognize and bind to the certain regions of DNA or histones that were modified by epigenetic writers. Epigenetic readers can be subdivided into three main groups: DNA methylation readers, histone methylation readers and histone acetylation readers. DNA methylation readers can identify methylated DNA
Epigenetic erasers
Epigenetic erasers are proteins responsible for removing modifications to histones and DNA generated by epigenetic writers to regulate gene expression. The most studied family of epigenetic erasers is that of histone deacetylases (HDACs) [18], [199].
Conclusions and future perspectives
A decade that has passed after the publication of the extended version of “Hallmarks of cancer” was associated with the unforeseen progress in cancer research and acquisition of large volume of new data. It was revealed that the process of cancer development was not only based on the genomic instability, but also mutation-free epigenetic changes. Therefore, nonmutational epigenetic reprogramming was recently suggested to be included in the updated classification of “cancer hallmarks”. The
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
W.H.A. acknowledges financial support from Ministry of Education Singapore (Project No. A-0004134-00-00 and A-0004539-00-00). M.V.B. acknowledges financial support from City University of Hong Kong (Project No.7005614 and 9610518) and Pneumoconiosis Compensation Fund Board (Project No. 9211315). The authors acknowledge Tibor Hajsz for help with the generation of Figure 1.
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