1. INTRODUCTION.
The control of chromatin structure mediated by epigenetic mechanisms has
an accepted role in the control of gene expression and other DNA-related
biological processes. DNA methylation/demethylation and
post-translational modifications of histones set an epigenetic landscape
that is stable during cell replication and that could be modulated by
specific environmental signals to guide normal development and cell
differentiation (Allis and Jenuwein, 2016; Dai et al., 2020). This
orchestrated setting is also subject to deviations. Epigenetic
alterations are associated with multiple human disorders, includingde novo epimutations (e.g., cancer, neurological disorders,
infectious diseases or cardiovascular pathologies) but also
germline-related diseases (e.g. rare disorders associated with genetic
mutations affecting epigenetic modifiers) (Berdasco and Esteller, 2018).
Our knowledge of epigenetic alterations in disease has improved the
discovery and development of small-molecule compounds targeting the
catalytic pocket of enzymes with epigenetic activity (Ganesan et al.,
2019; Jones et al., 2019). The range of small-molecule inhibitors that
target epigenetic proteins include enzymes that add chemical groups into
DNA and histones (“writers ”), proteins that remove these
chemical tags (“erasers” ) and specific binding domain proteins
that are able to identify and interpret these modifications
(“erasers” ) (Ganesan, 2018; Ganesan et al., 2019). DNA
methyltransferase (DNMT) inhibitors such as decitabine have been
implemented into clinical practice for the treatment of haematological
malignancies, such as myelodysplastic syndromes (MDS), acute myeloid
leukaemia (AML), and chronic myeloid leukaemia (CML) (Prebet et al.,
2014; Diesch et al., 2016). Similarly, histone deacetylase (HDAC)
inhibitors have also reached FDA- approval for clinical routine in
refractory CML Panobinostat) (Cavenagh and Popat, 2018). New approaches
in epidrug development explore the presence of genetic mutations of
epigenome-modifying enzymes as a more targeted therapy (Cossío et al.,
2020). In this line, the histone methyltransferase (HMT) EZH2 inhibitor
tazemotostat reached a Phase II/III clinical trial to treat refractory
non-Hodgkin lymphoma with EZH2 amplification (Italiano et al., 2018) or
the DOT1L inhibitor pinometostat for the treatment of MLL-fusion
leukaemia (Stein et al., 2018). Opportunities have extended beyond
cancer and the potential of epigenetic drugs as therapeutic agents able
to revert epigenetic defects is extending to other pathologies, ranging
from infectious diseases to brain diseases, cardiovascular and metabolic
disorders (Ballestar and Li, 2017; Berdasco and Esteller, 2019;
Villanueva et al., 2020). The volume of epigenetic research conducted in
academia, R&D sector of pharmaceutical industry and biotech companies
have boosted the epigenetic-based market.
Following the epigenetic model, recent discoveries on the role of
post-translational modifications at the RNA level (termed
“epitranscriptome”) have opened new possibilities for the
pharmacological targeting of these modifications as an intervention
strategy in human diseases with aberrant epitranscriptomes. Over the
last 50 years more than 140 posttranslational modifications in RNA
molecules have been identified (Boccaletto et al., 2018), most of them
affecting the most abundant RNAs: ribosomal RNA (rRNA) andtransfer RNA (tRNA) (Roundtree et al., 2017a). However, it is
only during the past decade have we started to construct the first maps
of messenge r RNA (mRNA) modifications and to envision their
impact on gene regulation.
The four RNA bases (A, T, C, U) as well as the ribose sugar can harbour
modification sites that range from base isomerization processes to
chemical modifications, including inosine (I), 5‑methyl cytidine (m5C;
also known as 5mC), 5‑hydroxylmethyl cytidine (hm5C; also known as
5hmC), pseudo-uridine (Ψ), N6-methyladenosine (m6A) and
N1-methyladenosine (m1A). Nowadays, we have identified and characterized
mRNA posttranslational modifications that are known to be important for
RNA biogenesis, RNA dynamism and RNA function under physiological
conditions. In addition, their impact on the onset and progression of
human diseases, especially cancer, has been recently examined. Despite
all efforts, the field of epitranscriptomics is still in its infancy and
we are still far from obtaining a complete landscape of RNA
modifications and the molecular and biological pathways in which they
are involved. What is clear from the latest evidences, however, is that
RNA does not merely act as an effector molecule but it has an active
role in the regulation of gene expression. In this review, we will
describe the principal RNA modifications (with a focus on mRNA),
summarize the latest scientific evidences of their dysregulation in
cancer and provide an overview of the state-of-the-art drug discovery
efforts. Finally, we will discuss the principal challenges in the field
of chemical biology and drug development to increase the potential of
targeted-RNA for clinical benefit.