Review
Histone modifications as a pathogenic mechanism of colorectal tumorigenesis

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Abstract

Epigenetic regulation of gene expression has provided colorectal cancer (CRC) pathogenesis with an additional trait during the past decade. In particular, histone post-translational modifications set up a major component of this process dictating chromatin status and recruiting non-histone proteins in complexes formed to “handle DNA”. In CRC, histone marks of aberrant acetylation and methylation levels on specific residues have been revealed, along with a plethora of deregulated enzymes that catalyze these reactions. Mutations, deletions or altered expression patterns transform the function of several histone-modifying proteins, further supporting the crucial role of epigenetic effectors in CRC oncogenesis, being closely associated to inactivation of tumor suppressor genes. Elucidation of the biochemical basis of these new tumorigenic mechanisms allows novel potential prognostic factors to come into play. Moreover, the detection of these changes even in early stages of the multistep CRC process, along with the reversible nature of these mechanisms and the technical capability to detect such alterations in cancer cells, places this group of covalent modifications as a further potential asset for clinical diagnosis or treatment of CRC. This review underlines the biochemistry of histone modifications and the potential regulatory role of histone-modifying proteins in CRC pathogenesis, to date. Furthermore, the underlying mechanisms of the emerging epigenetic interplay along with the chemical compounds that are candidates for clinical use are discussed, offering new insights for further investigation of key histone enzymes and new therapeutic targets.

Introduction

Being one of the most common types of malignancy, along with one of the most frequent etiologies of cancer mortality in both genders worldwide, colorectal cancer (CRC) still presents a major public health problem to confront and a rapidly evolving research field to keep up with (Jemal et al., 2011, Siegel et al., 2012). Nevertheless, it is well established that sporadic and hereditary CRC constitute the histological and clinical outcome of a multistage, though hierarchically structured, genetic process characterized by the sequential accumulation of genetic and epigenetic alterations (Fearon and Vogelstein, 1990).

CRC genetic alterations present a well studied field over the past three decades providing an overall paradigm of the multistep carcinogenesis process. Driver mutations affect major intracellular signaling pathways implicated in proliferation, differentiation, cell adhesion and migration, apoptosis, DNA stability and repair (Saif and Chu, 2010).

Focusing on epigenetic alterations, a recently evolving research area, accumulating data indicate an additional trait of CRC pathogenesis. The term epigenetics refers to heritable changes that although not affecting DNA sequence, they play a critical regulatory role in gene expression. Epigenetic changes include DNA methylation, loss of imprinting, post-translational histone modifications, nucleosome positioning, chromatin looping and small non-coding RNAs interference (van Engeland et al., 2011). Among these alterations, the most extensively characterized is aberrant DNA methylation including both global DNA hypomethylation, an age-dependent process with poor prognosis occurring at early stages in CRC (Suzuki et al., 2006), and CpG island hypermethylation, presenting an additional hit in the classic Knudson genetic model (Knudson, 2001) for inactivation of tumor suppressor genes (Herman and Baylin, 2003), with main example the mismatch repair gene MutL homolog 1 (MLH1) implicated in CRC pathogenesis (Herman et al., 1998). Although individually studied, a complex interplay has emerged between DNA methylation and histone modifications that is mediated by biochemical interactions of histone and DNA methyltransferases (HMTs and DNMTs, respectively) with the recruitment of histone deacetylases (HDACs) (Cedar and Bergman, 2009, Tachibana et al., 2008, Zhao et al., 2009). Taking all these into account, an additional epigenetic phenotype has been attributed to CRC that is critically regulated by the post-translational modifications of histone residues, allowing the generation of a corresponding multistep epigenetic CRC model, with potential novel therapeutic targets.

The present review explores the biochemistry behind histone modifications and the respective regulatory role of histone-modifying proteins in CRC pathobiology. In addition, the underpinning mechanisms of the emerging epigenetic interplay along with targeted therapy in research are discussed, providing new insights for further investigation of pivotal histone enzymes and new mechanisms in favor of pharmaceutical treatment. Although the types of histone modifications will be described in separate sections for comprehensive purposes, one should bear in mind that these changes and the underlying mechanisms take place simultaneously or in parallel and are exposed to a constant and mutual regulation.

Section snippets

Biochemical basis of post-translational histone modifications in CRC

The basic nucleosome unit is composed of four core histone proteins, H2A, H2B, H3 and H4, that form an octamer around which a segment of DNA winds with 147 base pairs in 1.67 left-handed superhelical turns. Highly basic histone N-terminal domains are able to protrude from the nucleosome establishing contact with adjacent ones (Fig. 1). At least eight different types of modifications have been characterized on multiple sites of specific residues of the “free” N-terminal domains, notably lysine

Mechanisms of acetylation marks in CRC

Acetylation takes place in lysine residues of the four core histones, balanced by the opposite effects of two main enzymatic groups, the histone acetyltransferases (HATs) and the HDACs. H3 and H4 histone acetylation levels are crucial regarding chromatin status and the regulation of gene expression, being generally associated with active gene transcription (Kouzarides, 2007). Functionally, an adequate acetylation levels either change the electrostatic charge of histones and therefore the

HATs

HATs are largely known as important transcription co-activators recruited by transcription factors, capable to acetylate histones and non-histone proteins (Grunstein, 1997, Santos-Rosa and Caldas, 2005, Yang, 2004) (Fig. 2). HATs recruit acetyl-CoA in order to catalyze an acetyl group's transfer to lysine side chain's ɛ-amino group, thus converting the lysine's positive charge into neutral and, consequently, reducing histone–DNA affinity. They are divided into three main families: the

Mechanisms of methylation marks in CRC

Histone methylation takes place either on lysines or arginines. This dual residue targeting, along with multiple marks on the same residue such as mono-, di- and tri-methylation for lysines and mono- and di-methylation for arginines, lays extra complexity to the process (Kouzarides, 2007, Martin and Zhang, 2005). Enzymes mediating this modification are distinguished into lysine and arginine HMTs and lysine histone demethylases (HDMs). Functional complexity persists, since these

Lysine HMTs

HMTs may also acquire abnormal expression profiles and biological behavior linked to CRC oncogenic process (Ellis et al., 2009) (Table 4). The H3K4 myeloid/lymphoid leukemia (MLL) family of lysine HMTs is rather well studied due to the MLL1 proto-oncogene involved in myeloid and lymphoid leukemia (Krivtsov and Armstrong, 2007). A wide consensus coding sequence analysis revealed six somatic heterozygous mutations in MLL3 among 35 CRC tumors, two of them leading to truncation of the catalytic SET

Epigenetic alterations interplay in CRC

The ensemble of the histone modification mechanisms described do not act independently during CRC tumorigenesis, but are rather subjected to a dynamic crosstalk between other epigenetic events, such as DNA methylation and microRNAs (miRNAs). The continuous interaction of epigenetic mechanisms originates from the process that defines gene repression patterns during mammalian development, being mediated by biochemical interactions between HMT SET domain and DNMTs. More specifically, it is

Regulation of histone modifications in clinical practice

Histone dynamic alterations during the process of carcinogenesis increasingly emerge as mechanisms of great significance. Their reversible nature renders them prominent targets for pharmaceutical therapy and a number of clinical trials focused on several enzymes have been reported. The most thoroughly investigated agents are HDAC inhibitors (HDACi) (Bolden et al., 2006). HDACi can effectively suppress HDAC enzymatic activity of classes I and II confirming their important role in colon cell

Conclusions and future prospects

CRC follows an ultimate genetic model, in which a significant amount of knowledge has been acquired in favor of an overall approach of cancer biology, during the last years. Current epigenetic data elaborate further this model providing new insights, additional complexity and better understanding of the oncogenic process. Aberrant post-translational histone modifications play a key role in this model, linking the function of other epigenetic categories, but also elucidating further aspects of

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