Research Article: Cancer epigenetics: Moving forward

Date Published: June 7, 2018

Publisher: Public Library of Science

Author(s): Angela Nebbioso, Francesco Paolo Tambaro, Carmela Dell’Aversana, Lucia Altucci, John M. Greally

Abstract: Defects in chromatin modifiers and remodelers have been described both for hematological and solid malignancies, corroborating and strengthening the role of epigenetic aberrations in the etiology of cancer. Furthermore, epigenetic marks—DNA methylation, histone modifications, chromatin remodeling, and microRNA—can be considered potential markers of cancer development and progression. Here, we review whether altered epigenetic landscapes are merely a consequence of chromatin modifier/remodeler aberrations or a hallmark of cancer etiology. We critically evaluate current knowledge on causal epigenetic aberrations and examine to what extent the prioritization of (epi)genetic deregulations can be assessed in cancer as some type of genetic lesion characterizing solid cancer progression. We also discuss the multiple challenges in developing compounds targeting epigenetic enzymes (named epidrugs) for epigenetic-based therapies. The implementation of acquired knowledge of epigenetic biomarkers for patient stratification, together with the development of next-generation epidrugs and predictive models, will take our understanding and use of cancer epigenetics in diagnosis, prognosis, and treatment of cancer patients to a new level.

Partial Text: Although the complete sequence of the 3 billion base pairs that make up the human genome has been generated thousands of times [1,2], identifying genomic variations across the cell types that contribute to health and disease remains a major challenge.

The transcriptional expression of a given locus is to a large extent determined by chromatin conformation: the region must be accessible to regulatory factors and transcriptional machinery. The homeostatic chromatin network is determined by the close interplay between polycomb family repressors, trithorax family activators, and chromatin remodelers [11] (Fig 1). Mutations in genes coding for these factors impact strongly on epigenetic homeostasis, and deregulation can lead to tumorigenesis. For example, active loci are associated with TFs and chromatin modifiers such as KDM, p300, ARID1A/B, and MLL components, which trigger transcriptional activity. Mutations in MLL1 and CBP/p300 block correct commitment of regulatory regions in leukemia. In particular, leukemia-associated translocations involving MLL1 generate fusion protein-driven malignant transformation, which is controlled by HOX family genes and the HOX cofactor MEIS1 [12]. Further, gain-of-function EZH2 mutations were found in several lymphomas, characterized by aberrant histone H3 trimethylation at amino acid position 27 (H3K27me3) that block B-cell development [13] due to repression of lineage-specific developmental B-cell genes [14,15]. Repressive states of chromatin can persist throughout cell divisions by the action of specific histone modifications, DNA methylation, regulatory proteins, and non-coding RNA [16]. Active chromatin-remodeling enzymes are inactive in many human cancers, promoting global chromatin restriction. However, in many neoplasias, the aberrant CpG island methylator phenotype (CIMP) can suppress tumor suppression genes (TSGs) such as p16, as well as DNA mismatch repair genes, including MLH1 and MSH2 [17]. DNA hypermethylation reduces binding of the transcriptional repressor CTCF, causing insulator dysfunction frequent in Isocitrate Dehydrogenase (IDH) mutant gliomas [18]. IDH mutants have highlighted the tight crosstalk between epigenetics and metabolism via the formation of a so-called “oncometabolite,” 2-hydroxyglutarate, which is a competitive inhibitor of α-ketoglutarate(KG)–dependent enzymes, such as TET2, leading to DNA and histone hypermethylation and a differentiation block [19]. Thus, the response of a locus to stimuli depends on the expression and binding of specific TFs to regulatory regions. Once bound to DNA, TFs can also modify the chromatin landscape, recruiting chromatin modifying and remodeling enzymes. In this scenario, TFs such as RUNX1, RARα, and CBFB (and their oncogenic derivatives) provide clear examples of transcriptional and epigenetic reprogramming driving leukemogenesis [20]. Different cues can result in aberrantly permissive or restrictive chromatin states that can lead to oncogene activation or tumor suppressor inactivation, enabling cells to acquire the six essential hallmarks of cancer [6] (Fig 1).

The hallmarks of human cancer (proliferative signals, cell death impairment, inactivation of growth suppressors, angiogenesis, replicative independence leading to immortality, and acquirement of cancer progression features such as invasion and metastasis) were defined by Hanahan and Weinberg as the driving forces of tumorigenesis [6,21]. These hallmarks identified cancer as a disease of the genome. The fact that the classical hallmarks of human cancer can potentially be achieved “purely” through epigenome deregulation [18] questions the current view of tumorigenesis, suggesting that epigenome deregulation may cause cancer without genetic contribution.

The role of genetic and epigenetic alterations in cancer was initially discovered in hematological malignancies, heterogeneous disorders characterized by arrest of differentiation and uncontrolled proliferation of hematopoietic stem cells (HSCs). Gene expression and genome-wide DNA methylation profiles have become precise tools for cell type prediction throughout hematopoietic lineage in health and disease. By clarifying the role of epi-modifications in hematopoiesis, a significant step forward in precision medicine for blood cancers has been made.

Unraveling epigenetic and genetic changes involved in cancer pathogenesis has always been, and to a large extent still is, a huge task. We are currently gaining greater insights into how the epigenome determines cell type specification, development, and pathology. IHEC results have shed new light on molecular mechanisms of disease, highlighting the fundamental challenges in understanding causal networks between genotype and phenotype. Epigenome profiles are also able to define distinct cellular identities and specific cell–cell interactions driving tumorigenesis. Acquired knowledge and its exploitation in preclinical and clinical settings for hematological malignancies, as well as common adult solid cancers (such as BC) and pediatric tumors (including RT), is just an example of the headway made in cancer epigenetics. There is still an urgent need to translate the findings to the clinic, where they may be used for diagnostic, prognostic, and treatment response evaluation. While for some cancers (such as those described here), this is already (or just one step away from) reality, for others further developments are still required.



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