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Epi-Drugs Targeting RNA Dynamics in Cancer

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Cancer Research: An Interdisciplinary Approach

Part of the book series: Interdisciplinary Cancer Research ((ICR,volume 1))

Abstract

From the early discovery of ribonucleic acid in 1868, the RNA world has seen constant evolution. To date, more than ten types of RNA species are recognized and have been shown to regulate a plethora of physiological processes, including transcription and splicing. In addition, a crucial role for RNA modifications (epitranscriptomics) in RNA dynamics has also started to be unraveled. The deposition of N6-methyladenosine (m6A) mark has demonstrated to dramatically influence the RNA transcripts’ stability as well as their functioning and processing. Notably, altered RNA levels and the aberrant distribution of m6A have been reported in cancer, and convincing evidence supports their role in oncogenesis. Thus, the idea of targeting the RNA dynamics to rescue the correct RNA metabolism led to the recent development of several epigenetic drugs (epidrugs). Currently, only some of these epigenetic drugs have shown great efficiency and reached clinical trials. However, efforts to improve their specificity and reduce side effects are ongoing. In this context, new hopes are coming from the epitranscriptomic landscape and the expanding universe of epigenetic factors. RNA-modifying enzymes can be novel molecular targets, broadening the horizons for drug discovery. In this chapter, we will discuss the role of different RNA classes and m6A modification in biological processes that affect transcription as well as their involvement in cancer and the applicability of epidrugs for future therapeutic interventions.

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Abbreviations

TUT4:

3′ terminal uridylyl transferase

5caC:

5-Carboxylcytosine

5fC:

5-Formylcytosine

5hmC:

5-Hydroxymethylcytosine

m7G:

7-Methylguanosine

AML:

Acute myeloid leukemia

ADAR:

Adenosine deaminase acting on RNA

ALKBH5:

AlkB Homolog 5, RNA Demethylase

APA:

Alternative polyadenylation sites

AS:

Alternative splicing

AR:

Androgen receptor

AON:

Antisense mutation-specific oligonucleotide

asRNAs:

Antisense RNAs

U2AF:

Auxiliary Factor of U2

BBP:

Branchpoint Binding Protein

BIN1:

Bridging Integrator 1

CTCF:

CCCTC-binding factor

CLCN1:

Chloride Voltage-Gated Channel 1

circRNAs:

Circular RNAs

CRC:

Colon rectal cancer

CPSF:

Cleavage and poly (A) adenylation specificity factor

CstF:

Cleavage stimulation factor

CTD :

C-terminal domain

USP7:

Deubiquitinated by the ubiquitin-specific peptidase 7

DGCR5:

DiGeorge syndrome critical region gene 5

DNMTs:

DNA methyltransferases

HAKAI:

E3 ubiquitin-protein ligase

EZH2:

Enhancer of zeste homolog 2

eRNAs:

Enhancer RNA

epidrugs:

Epigenetic drugs

EMT :

Epithelial-mesenchymal transition

ESCC:

Esophageal squamous cell carcinoma

EX:

Exon skipping

FTO:

Fat Mass and Obesity-related transcript

FGFR2 :

Fibroblast Growth Factor Receptor 2

FDA:

Food and Drug Administration

GMP:

Guanosine monophosphate

HDACi:

HDAC inhibitors

HCV:

Hepatitis C virus

HP1:

Heterochromatin protein 1

hnRNPG :

Heterogeneous nuclear ribonucleoprotein G

HDACi:

Histone deacetylase

IGF2BPs:

Insulin-like growth factor 2 mRNA-binding proteins

IR:

Intron retention

IDHs:

Isocitrate dehydrogenases

KLK3:

Kallikrein Related Peptidase 3

lncRNAs:

Long ncRNAs

MA:

Meclofenamic acid

mRNA :

Messenger RNA

5mC:

Methylation in position 5 of cytosine

METTL:

Methyltransferase

METTL3i:

METTL3 inhibitors

miRNA:

MicroRNA

MLL:

Mixed-lineage leukemia

MRG15:

MORF-related gene on chromosome 15

MUC1:

Mucin 1

ME:

Mutually exclusive

MDS:

Myelodysplastic syndrome

Mcl-1:

Myeloid cell leukemia-1

DM:

Myotonic dystrophy

m6A:

N6-methyladenosine

ncRNA :

Noncoding RNAs

PAP:

poly-A polymerase

PolyA:

polyadenylation

PR C2:

Polycomb Repressive complex 2

PTB/hnRNPI:

Polypyrimidine tract binding protein

PIC :

Pre-initiation complex

ψ:

Pseudouridine

PKM:

Pyruvate kinase

R-2HG:

R-2-hydroxyglutarate

snRNPs:

Ribonucleoproteins

rRNA :

Ribosomal RNA

RBM15/15B:

RNA Binding Motif Protein 15

piRNA:

RNA interacting with PIWI

epitranscriptomics:

RNA modifications

Pol :

RNA polymerases

SAM:

S-adenosylmethionine

SRSF3:

Ser-/Arg-rich splicing factor 3

SRSF10:

Serine and Arginine Rich Splicing Factor 10

SRSF6:

Serine-/arginine-rich splicing factor 6

siRNA:

Small interfering RNA

snRNA:

Small nuclear RNA

snoRNA:

Small nucleolar RNA

T-ALL:

T cell acute lymphoblastic leukemia

TBP :

TATA-binding protein

TET:

Ten-Eleven Translocation

TFs :

Transcription factors

TSS :

Transcription start site

tRNA:

Transfer RNA

TNP2:

Transition nuclear protein 2

VIRMA:

Vir Like m6A Methyltransferase Associated

YTHs:

YTH-family of m6A reader proteins

ZC3H13:

Zinc Finger CCCH-Type Containing 13

ZEB:

Zinc finger E-box-binding homeobox

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Acknowledgment and Funding

This work was supported by FISR2019_00374 MeDyCa-B84G19000200008; Campania Regional Government FASE 2: IDEAL (CUP B63D18000560007); MISE: Nabucco Project; and VALERE: Vanvitelli per la Ricerca Program: EPInhibitDRUGre (CUP B66J20000680005). N.D.G. was supported by PON Ricerca e Innovazione 2014–2020 Linea 1, AIM (AIM1859703).

Authors’ Contributions

The work reported in the paper has been performed by the authors, unless clearly specified in the text.

Project administration, Supervision and Writing: L.A. and C.D. Conceptualization and Writing: N.D.G, C.D, G.B, I.L, G.S Review and Editing N.D.G., L.A. and C.D. All authors read and approved the final manuscript.

Competing Interests

The authors declare that they have no competing interests.

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Authors and Affiliations

  1. Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy

    Guglielmo Bove, Ida Lettiero, Giulia Sgueglia, Nunzio Del Gaudio, Lucia Altucci & Carmela Dell’Aversana

  2. BIOGEM, Ariano Irpino, Italy

    Lucia Altucci

  3. Institute Experimental Endocrinology and Oncology “Gaetano Salvatore”, National Research Council (CNR), Naples, Italy

    Lucia Altucci & Carmela Dell’Aversana

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  1. Guglielmo Bove
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  2. Ida Lettiero
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  3. Giulia Sgueglia
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  4. Nunzio Del Gaudio
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  5. Lucia Altucci
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  6. Carmela Dell’Aversana
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Corresponding authors

Correspondence to Lucia Altucci or Carmela Dell’Aversana .

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Editors and Affiliations

  1. Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Stockholm, Sweden

    Nima Rezaei

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Bove, G., Lettiero, I., Sgueglia, G., Del Gaudio, N., Altucci, L., Dell’Aversana, C. (2023). Epi-Drugs Targeting RNA Dynamics in Cancer. In: Rezaei, N. (eds) Cancer Research: An Interdisciplinary Approach. Interdisciplinary Cancer Research, vol 1. Springer, Cham. https://doi.org/10.1007/16833_2022_113

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