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RNA editing-dependent epitranscriptome diversity in cancer stem cells

Key Points

  • Methylation of RNA at N6-methyladenosine (m6A) has been identified in humans, viruses and mice and has been linked to several diseases.

  • m6A plays an important role in pluripotency and differentiation and has therefore been associated with cancer development; it can promote the translation of several oncogenes.

  • Malignant adenosine-to-inosine RNA editing controls the self-renewal of cancer stem cells (CSCs), and raises the possibility that targeting this pathway may provide a new strategy for eliminating CSCs.

  • RNA splicing disruption promotes generation of aberrant splice isoforms in pre-malignant and malignant haematopoietic disorders and is a key therapeutic vulnerability in a growing number of human malignancies.

  • Therapeutic splicing modulation has the potential to target bulk tumour cells as well as self-renewing CSCs that contribute to disease progression and relapse.

Abstract

Cancer stem cells (CSCs) can regenerate all facets of a tumour as a result of their stem cell-like capacity to self-renew, survive and become dormant in protective microenvironments. CSCs evolve during tumour progression in a manner that conforms to Charles Darwin's principle of natural selection. Although somatic DNA mutations and epigenetic alterations promote evolution, post-transcriptional RNA modifications together with RNA binding protein activity (the 'epitranscriptome') might also contribute to clonal evolution through dynamic determination of RNA function and gene expression diversity in response to environmental stimuli. Deregulation of these epitranscriptomic events contributes to CSC generation and maintenance, which governs cancer progression and drug resistance. In this Review, we discuss the role of malignant RNA processing in CSC generation and maintenance, including mechanisms of RNA methylation, RNA editing and RNA splicing, and the functional consequences of their aberrant regulation in human malignancies. Finally, we highlight the potential of these events as novel CSC biomarkers as well as therapeutic targets.

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Figure 1: Epitranscriptome regulation contributes to cancer stem cell generation.
Figure 2: Consequences of RNA editing by ADAR.
Figure 3: Translational control by MSI2 directs normal and leukaemic stem cell function.
Figure 4: RNA processing in normal and malignant haematopoiesis.

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Acknowledgements

The authors acknowledge the inspiration and support of their patients and their professional colleagues. This work was supported by the Moores Foundation, California Institute for Regenerative Medicine (CIRM) grants (RN2-00910-1, DR1-01430 and RS1-00228-1); CIRM Training Grant (TG2-01154); National Institutes of Health (NIH) National Institute of General Medical Sciences grant 5K12GM068524; NIH National Cancer Institute (NCI) grant 2P30CA023100-28; NIH NCI grants R01CA205944, R21CA189705 and R21CA194679; the Leukemia & Lymphoma Society (0754-14); the Sanford Stem Cell Clinical Center; the San Diego Foundation; the Ratner Family Foundation; and the Swedish Childhood Cancer Foundation (Barncancerfonden).

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Correspondence to Catriona H. M. Jamieson.

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C.H.M.J. receives research funding by sponsored research agreement with GlaxoSmithKline (GSK DPAc001) and a laboratory service agreement with Johnson & Johnson (#15-0230). The other authors declare no competing interests.

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FURTHER INFORMATION

DARNED

RADAR

PowerPoint slides

Glossary

5′-Untranslated regions

(UTRs). Located upstream of the translation initiation codon, the 5′-UTRs are important for translational regulation of mRNA transcripts.

3′-UTRs

(Untranslated regions). The 3′-UTRs have an important role in regulation of gene expression by controlling RNA degradation, cellular localization and translation.

Alu elements

A class of SINE elements, Alu elements comprise approximately 10% of the human genome. Inverted Alu elements are favourable targets of adenosine deaminase acting on double-stranded RNA (ADAR)-mediated RNA editing; as much as 90% of adenosine-to-inosine editing in the human transcriptome occurs within Alu elements.

Short interspersed nuclear element

(SINE). Presented at high frequency in the eukaryotic genome, SINEs are short (<700 bp) non-coding DNA sequences that retrotranspose themselves by a copy and paste mechanism.

Long interspersed nuclear elements

(LINEs). Similar to SINEs, LINEs are a class of retrotransposons (6kb) comprising approximately 17% of the human genome. They consist of a 5′-untranslated region (UTR), two open reading frames (ORF1 and ORF2) and a 3′-UTR. Misregulation of LINEs has been linked to tumorigenesis by retrotransposition-dependent and -independent functions.

Primary microRNAs

(Pri-miRNAs). The miRNA genes are transcribed by RNA polymerase II and cleaved to large pri-miRNA transcripts that are subsequently cleaved by DROSHA to form the precursor miRNA (pre-miRNA) transcripts.

Precursor microRNAs

(Pre-miRNAs). Pre-miRNA transcripts are exported from the nucleus by exportin 5 (XPO5), to be processed by DICER1 to form the mature miRNAs.

Blast crisis (BC) CML

BC CML is characterized by the elevated numbers of self-renewing cancer stem cells residing in the granulocyte–macrophage progenitor compartment, which express higher levels of the BCR–ABL1 oncogene and nuclear β-catenin. Patients with BC live an average of 3–6 months.

Crosslinking immunoprecipitation

(CLIP). CLIP is UV crosslinking followed by immunoprecipitation to examine the interactions between RNA transcripts and RNA binding proteins and location of RNA modifications. The isolated RNA is reverse transcribed for PCR, microarray or sequencing analysis.

LINSCA1+KIT+ cells

These cells are lineage-negative (LIN), stem-cell antigen 1 positive (SCA1+) and KIT positive (KIT+) and make up a population of mouse bone marrow cells (0.5%) with long-term multi-lineage repopulation capacity.

Accelerated phase CML

(AP CML). In this phase of chronic myeloid leukaemia (CML), the cancer stem cells often acquire new genetic mutations, causing more severe symptoms and poor response to treatment.

Chronic phase CML

(CP CML). The beginning phase of chronic myeloid leukaemia (CML) in which the patients have acquired the BCR–ABL1 oncogene, which induces abnormal production of myeloid cells. The standard treatment for CP CML is tyrosine kinase inhibitors such as imatinib or dasatinib. However, CP CML can progress slowly to an accelerated phase and later a blastic phase (blast crisis) over several years.

Branch site

Also called branch point; these occur predominantly at adenosine, highly conserved and closely localized to the 3′-splice site of an intron. The consensus sequence for an intron branch site (in IUPAC nucleic acid notation) is Y-U-R-A-C (20–50 nucleotides upstream of the acceptor site). Intronic RNA editing events, point mutations in the underlying DNA or errors during transcription have the potential to either destroy a branch site or activate a cryptic splice site in part of the transcript that is usually not spliced.

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Jiang, Q., Crews, L., Holm, F. et al. RNA editing-dependent epitranscriptome diversity in cancer stem cells. Nat Rev Cancer 17, 381–392 (2017). https://doi.org/10.1038/nrc.2017.23

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