Abstract
Over 170 chemical modifications have been identified in protein-coding and noncoding RNAs and shown to exhibit broad impacts on gene expression. Dysregulation of RNA modifications caused by aberrant expression of or mutations in RNA modifiers aberrantly reprograms the epitranscriptome and skews global gene expression, which in turn leads to tumorigenesis and drug resistance. Here we review current knowledge of the functions and underlying mechanisms of aberrant RNA modifications in human cancers, particularly several common RNA modifications, including N6-methyladenosine (m6A), A-to-I editing, pseudouridine (ψ), 5-methylcytosine (m5C), 5-hydroxymethylcytosine (hm5C), N1-methyladenosine (m1A), and N4-acetylcytidine (ac4C), providing insights into therapeutic implications of targeting RNA modifications and the associated machineries for cancer therapy.
Highlights
The research on RNA modifications began in the 1950s with the discovery of pseudouridine (ψ, known as the fifth RNA nucleotide) (Davis & Allen 1957)
We found that METTL14 was critical for Acute myeloid leukemia (AML) initiation and maintenance, as well as for the self-renewal of leukemia stem cells (LSCs) and drug response of AML cells, by regulating its important target transcripts such as MYB and MYC in an m6A-dependent manner (Weng et al 2018)
We recently identified IGF2 mRNA-binding proteins (IGF2BPs) as m6A readers and showed that they could recognize and bind to the coding region instability determinant of MYC messenger RNAs (mRNAs) in an m6A-dependent manner, leading to the increased expression of MYC (Huang et al 2018)
Summary
The research on RNA modifications began in the 1950s with the discovery of pseudouridine (ψ, known as the fifth RNA nucleotide) (Davis & Allen 1957). Since 2012, numerous next-generation sequencing (NGS) methods have been developed for the transcriptome-wide detection of widespread and conserved RNA modifications in messenger RNAs (mRNAs), including N6-methyladenosine (m6A) (Dominissini et al 2012, Linder et al 2015, Meyer et al 2012), N6, 2 -O-dimethyladenosine (m6Am) (Linder et al 2015), 5-methylcytosine (m5C) (Hussain et al 2013, Khoddami & Cairns 2013, Squires et al 2012), 5-hydroxymethylcytosine (hm5C) (Delatte et al 2016), N1methyladenosine (m1A) (Dominissini et al 2016, Li et al 2016), inosine (Suzuki et al 2015), N4-acetylcytidine (ac4C) (Arango et al 2018), and ψ (Carlile et al 2014, Schwartz et al 2014a) (Figure 1) Such profiling studies showed that RNA modifications could be cell context specific and dynamically fine-tuned during physiological processes, while many modifications sites are evolutionarily conserved. Exploration of the links between RNA modifications and human cancer in the hope of developing effective epigenetic therapies represents one of the new frontiers in cancer research
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