Mutual Correlation between Non-Coding RNA and S-Adenosylmethionine in Human Cancer: Roles and Therapeutic Opportunities.

Laura Mosca,Michele Caraglia,Marina Porcelli,Francesca Vitiello,Martina Pagano,Roberta Veglia Tranchese,Luigi Borzacchiello,Giovanna Cacciapuoti,Alessandra Coppola

doi:10.3390/cancers13133264

Laura Mosca, Michele Caraglia + Show 7 more

Open Access

https://doi.org/10.3390/cancers13133264

Copy DOI

Journal: Cancers	Publication Date: Jun 29, 2021
Citations: 8	License type: CC BY 4.0

Affiliation: University of Campania "Luigi Vanvitelli"

Abstract

Simple SummaryNon-coding RNAs and S-adenosylmethionine, the methyl donor required in all epigenetic methylation reactions, have emerged in recent years as crucial players in the modulation of gene expression in different types of human cancers. This review summarizes the most recent findings on reciprocal regulation between AdoMet and non-coding RNAs. AdoMet was found to exert anticancer activity through epigenetic regulation of non-coding RNAs, including microRNAs, long non-coding RNAs and circular RNAs. On the other hand, several microRNAs and long non-coding RNAs have been reported to display regulatory effects on the expression of genes involved in AdoMet synthesis and metabolism. Increasing knowledge on the relationship between AdoMet and non-coding RNAs will provide insights for further development of diagnostic and therapeutic strategies for cancer treatments.Epigenetics includes modifications in DNA methylation, histone and chromatin structure, and expression of non-coding RNAs (ncRNAs), especially microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). Knowledge of the relationships between S-adenosylmethionine (AdoMet or SAM), the universal methyl donor for all epigenetic methylation reactions and miRNAs or lncRNAs in human cancer may provide helpful insights for the development of new end more effective anticancer therapeutic approaches. In recent literature, a complex network of mutual interconnections between AdoMet and miRNAs or lncRNAs has been reported and discussed. Indeed, ncRNAs expression may be regulated by epigenetic mechanisms such as DNA and RNA methylation and histone modifications. On the other hand, miRNAs or lncRNAs may influence the epigenetic apparatus by modulating the expression of its enzymatic components at the post-transcriptional level. Understanding epigenetic mechanisms, such as dysregulation of miRNAs/lncRNAs and DNA methylation, has become of central importance in modern research. This review summarizes the recent findings on the mechanisms by which AdoMet and miRNA/lncRNA exert their bioactivity, providing new insights to develop innovative and more efficient anticancer strategies based on the interactions between these epigenetic modulators.

Highlights

This review summarizes recent findings on the regulatory role exerted by the methyl donor AdoMet on the expression of oncogenic or tumor-suppressor non-coding RNAs (ncRNAs), especially miRNAs and long noncoding RNAs (lncRNAs), as well as on the effects exerted by these compounds on the intracellular levels of AdoMet through the modulation of its metabolism
The findings indicated that the tumor suppressor activity of miR-203 is mediated by MAT2A and MAT2B downregulation and highlighted an oncogenic activity of MAT2B, linked to AKT activation [75]
Recent findings pointed out the correlation between lncRNAs and AdoMet in diethylnitrosamine-induced hepatocellular carcinoma (HCC) in rats, underlining how the administration of AdoMet at the beginning stages of HCC downregulated the expression of extra coding CCAAT/enhancerbinding protein alpha and of urothelial carcinoma related 1 (UCA1) gene transcripts and ameliorated histopathological alterations through downregulation of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway and upregulation of the antioxidant enzyme mRNA transcripts [86]

Summary

Introduction

Epigenetics deals with the mechanisms that directly affect gene expression without altering DNA sequences and is required to maintain normal growth and development in creativecommons.org/licenses/by/. The correlation between HCC development and reduced MTHFR activity has been reported in the work of Li C. et al [69], where the authors demonstrated that folatedeficiency conditions induced the upregulation of miR-149-5p and miR-22-3p and the inhibition of MTHFR expression in cancer cells, while maintaining protein levels in normal hepatocytes [69]. The authors demonstrated that in CRC AdoMet and its metabolite methylthioadenosine (MTA) inhibited IL-6/STAT3 signaling, reduced MAT2A and MAT2B expression, and upregulated miR-34a/b levels, resulting in increased apoptosis and decreased cell growth, migration, and metastasis [74]. These findings highlighted the oncogenic role of this circRNA, suggesting that the downregulation of has_circ_0007364 could be promising in cervical cancer treatment Taken together, this literature information strongly suggests that the modulation of ncRNAs involved in the dysregulation of AdoMet synthesis may represent an attractive therapeutic strategy to restore AdoMet levels and its regulatory effects against cancer progression.

AdoMet-Regulated ncRNAs in HUMAN Cancer and Their Role in Chemotherapy

Conclusions and and Perspectives