m 6 A RNA Methylation Regulators Contribute to Malignant Progression and Have Clinical Prognostic Impact in Gastric Cancer

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Abstract

N6-methyladenosine (m ⁶A) is the most common form of mRNA modification, and is dynamically regulated by the m ⁶A RNA methylation regulators. However, little is known about m ⁶A in gastric cancer. The aim of this work is to investigate the effects of m ⁶A RNA methylation regulators in gastric cancer. Here, we found that most of the 13 main m ⁶A RNA methylation regulators are higher expressed in 375 patients with gastric cancer. We identified two subgroups of gastric cancer (cluster1 and 2) by applying consensus clustering to m ⁶A RNA methylation regulators. Compared with the cluster1 subgroup, the cluster2 subgroup correlates with a poorer prognosis, and most of the 13 main m ⁶A RNA methylation regulators are higher expressed in cluster2. Moreover, the cancer-specific pathways are also significantly enriched in the cluster2 subgroup. This finding indicates that m ⁶A RNA methylation regulators are closely associated with gastric cancer. Based on this finding, we derived a risk signature, using 3 m ⁶A RNA methylation regulators (FTO, RBM15, ALKBH5), that is not only an independent prognostic marker but can also predict the clinicopathological features of gastric cancer. Moreover, FTO is higher expressed in high risk scores subtype in gastric cancer. Thus, this first finding provide us clues to understand epigenetic modification of RNA in gastric cancer.

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Methylated nucleotides block 5' terminus of HeLa cell messenger RNA.

C. Wei, A Gershowitz, B. Moss (1975)

Polyadenylylated [poly(A)+] mRNA from HeLa cells that were labeled with [3H-methyl]-methionine and 14C-uridine was isolated by poly(U)-Sepharose chromatography. The presence of approximately two methyl groups per 1000 nucleotides of poly(A)+ RNA was calculated from the 3H/14C ratios and known degrees of methylation of 18S and 28S ribosomal RNAs. All four 2'-O-methylribonucleosides, but only two base-methylated derivatives, 7-methylguanosine (7MeG) and 6-methyladenosine (6MeA), were identified. 6MeA was the major component accounting for approximately 50% of the total methyl-labeled ribonucleosides. 7MeG, comprising about 10% of the total, was present exclusively at the 5' terminus of the poly(A)+ RNA and could be removed by periodate oxidation and beta elimination. Evidence for a 5' to 5' linkage of 7MeG to adjacent 2'-O-methylribonucleosides through at least two and probably three phosphates to give structures of the type 7MeG5'ppp5pNMep- and 7MeG5'ppp5'NMepNmep- was presented. The previous finding of similar sequences of methylated nucleotides in mRNA synthesized in vitro by enzymes associated with virus cores indicates that blocked 5' termini may be a characteristic feature of mRNAs that function in eucaryotic cells.

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ALKBH5-dependent m6A demethylation controls splicing and stability of long 3'-UTR mRNAs in male germ cells.

Chong Tang, Rachel Klukovich, Hongying Peng … (2018)

N6-methyladenosine (m6A) represents one of the most common RNA modifications in eukaryotes. Specific m6A writer, eraser, and reader proteins have been identified. As an m6A eraser, ALKBH5 specifically removes m6A from target mRNAs and inactivation ofAlkbh5leads to male infertility in mice. However, the underlying molecular mechanism remains unknown. Here, we report that ALKBH5-mediated m6A erasure in the nuclei of spermatocytes and round spermatids is essential for correct splicing and the production of longer 3'-UTR mRNAs, and failure to do so leads to aberrant splicing and production of shorter transcripts with elevated levels of m6A that are rapidly degraded. Our study identified reversible m6A modification as a critical mechanism of posttranscriptional control of mRNA fate in late meiotic and haploid spermatogenic cells.

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Updates on Management of Gastric Cancer

Fabian Johnston, Michael Beckman (2019)

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Author and article information

Contributors

Jichang Hu: URI : http://loop.frontiersin.org/people/695327/overview

Journal

Journal ID (nlm-ta): Front Oncol

Journal ID (iso-abbrev): Front Oncol

Journal ID (publisher-id): Front. Oncol.

Title: Frontiers in Oncology

Publisher: Frontiers Media S.A.

ISSN (Electronic): 2234-943X

Publication date (Electronic): 18 October 2019

Publication date Collection: 2019

Volume: 9

Electronic Location Identifier: 1038

Affiliations

[1] ¹Department of Thoracic Surgery, Renmin Hospital of Wuhan University , Wuhan, China

[2] ²Division of Cardiothoracic Surgery, Central Hospital of EnShi Tujia and Miao Autonomous Prefecture, EnShi Clinical College of Wuhan University , EnShi, China

[3] ³Department of Pathology, Renmin Hospital of Wuhan University , Wuhan, China

Author notes

Edited by: Sungsoo Park, Department of Surgery, College of Medicine, Korea University, South Korea

Reviewed by: Ye Fu, Harvard University, United States; Fiona McMurray, University of Ottawa, Canada

*Correspondence: Jichang Hu hujichang@ 123456whu.edu.cn

This article was submitted to Gastrointestinal Cancers, a section of the journal Frontiers in Oncology

Article

DOI: 10.3389/fonc.2019.01038

PMC ID: 6813557

PubMed ID: 31681576

SO-VID: 6cf5ed53-cfd0-4139-988e-2d340c8a22db

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

History

Date received : 17 July 2019

Date accepted : 24 September 2019

Page count

Figures: 6, Tables: 0, Equations: 0, References: 40, Pages: 10, Words: 5609

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