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YTHDF2 facilitates UBXN1 mRNA decay by recognizing METTL3-mediated m(6)A modification to activate NF-κB and promote the malignant progression of glioma

BACKGROUND: The prognosis for diffuse gliomas is very poor and the mechanism underlying their malignant progression remains unclear. Here, we aimed to elucidate the role and mechanism of the RNA N6,2′-O-dimethyladenosine (m(6)A) reader, YTH N6-methyladenosine RNA binding protein 2 (YTHDF2), in regul...

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Autores principales: Chai, Rui-Chao, Chang, Yu-Zhou, Chang, Xin, Pang, Bo, An, Song Yuan, Zhang, Ke-Nan, Chang, Yuan-Hao, Jiang, Tao, Wang, Yong-Zhi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8272379/
https://www.ncbi.nlm.nih.gov/pubmed/34246306
http://dx.doi.org/10.1186/s13045-021-01124-z
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author Chai, Rui-Chao
Chang, Yu-Zhou
Chang, Xin
Pang, Bo
An, Song Yuan
Zhang, Ke-Nan
Chang, Yuan-Hao
Jiang, Tao
Wang, Yong-Zhi
author_facet Chai, Rui-Chao
Chang, Yu-Zhou
Chang, Xin
Pang, Bo
An, Song Yuan
Zhang, Ke-Nan
Chang, Yuan-Hao
Jiang, Tao
Wang, Yong-Zhi
author_sort Chai, Rui-Chao
collection PubMed
description BACKGROUND: The prognosis for diffuse gliomas is very poor and the mechanism underlying their malignant progression remains unclear. Here, we aimed to elucidate the role and mechanism of the RNA N6,2′-O-dimethyladenosine (m(6)A) reader, YTH N6-methyladenosine RNA binding protein 2 (YTHDF2), in regulating the malignant progression of gliomas. METHODS: YTHDF2 mRNA levels and functions were assessed using several independent datasets. Western blotting, quantitative polymerase chain reaction, and immunohistochemistry were used to evaluate the expression levels of YTHDF2 and other molecules in human and mouse tumor tissues and cells. Knockdown and overexpression were used to evaluate the effects of YTHDF2, methyltransferase-like 3 (METTL3), and UBX domain protein 1 (UBXN1) on glioma malignancy in cell and orthotopic xenograft models. RNA immunoprecipitation (RIP), methylated RIP, and RNA stability experiments were performed to study the mechanisms underlying the oncogenic role of YTHDF2. RESULTS: YTHDF2 expression was positively associated with a higher malignant grade and molecular subtype of glioma and poorer prognosis. YTHDF2 promoted the malignant progression of gliomas in both in vitro and in vivo models. Mechanistically, YTHDF2 accelerated UBXN1 mRNA degradation via METTL3-mediated m(6)A, which, in turn, promoted NF-κB activation. We further revealed that UBXN1 overexpression attenuated the oncogenic effect of YTHDF2 overexpression and was associated with better survival in patients with elevated YTHDF2 expression. CONCLUSIONS: Our findings confirmed that YTHDF2 promotes the malignant progression of gliomas and revealed important insight into the upstream regulatory mechanism of NF-κB activation via UBXN1 with a primary focus on m(6)A modification. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13045-021-01124-z.
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spelling pubmed-82723792021-07-12 YTHDF2 facilitates UBXN1 mRNA decay by recognizing METTL3-mediated m(6)A modification to activate NF-κB and promote the malignant progression of glioma Chai, Rui-Chao Chang, Yu-Zhou Chang, Xin Pang, Bo An, Song Yuan Zhang, Ke-Nan Chang, Yuan-Hao Jiang, Tao Wang, Yong-Zhi J Hematol Oncol Research BACKGROUND: The prognosis for diffuse gliomas is very poor and the mechanism underlying their malignant progression remains unclear. Here, we aimed to elucidate the role and mechanism of the RNA N6,2′-O-dimethyladenosine (m(6)A) reader, YTH N6-methyladenosine RNA binding protein 2 (YTHDF2), in regulating the malignant progression of gliomas. METHODS: YTHDF2 mRNA levels and functions were assessed using several independent datasets. Western blotting, quantitative polymerase chain reaction, and immunohistochemistry were used to evaluate the expression levels of YTHDF2 and other molecules in human and mouse tumor tissues and cells. Knockdown and overexpression were used to evaluate the effects of YTHDF2, methyltransferase-like 3 (METTL3), and UBX domain protein 1 (UBXN1) on glioma malignancy in cell and orthotopic xenograft models. RNA immunoprecipitation (RIP), methylated RIP, and RNA stability experiments were performed to study the mechanisms underlying the oncogenic role of YTHDF2. RESULTS: YTHDF2 expression was positively associated with a higher malignant grade and molecular subtype of glioma and poorer prognosis. YTHDF2 promoted the malignant progression of gliomas in both in vitro and in vivo models. Mechanistically, YTHDF2 accelerated UBXN1 mRNA degradation via METTL3-mediated m(6)A, which, in turn, promoted NF-κB activation. We further revealed that UBXN1 overexpression attenuated the oncogenic effect of YTHDF2 overexpression and was associated with better survival in patients with elevated YTHDF2 expression. CONCLUSIONS: Our findings confirmed that YTHDF2 promotes the malignant progression of gliomas and revealed important insight into the upstream regulatory mechanism of NF-κB activation via UBXN1 with a primary focus on m(6)A modification. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13045-021-01124-z. BioMed Central 2021-07-10 /pmc/articles/PMC8272379/ /pubmed/34246306 http://dx.doi.org/10.1186/s13045-021-01124-z Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Chai, Rui-Chao
Chang, Yu-Zhou
Chang, Xin
Pang, Bo
An, Song Yuan
Zhang, Ke-Nan
Chang, Yuan-Hao
Jiang, Tao
Wang, Yong-Zhi
YTHDF2 facilitates UBXN1 mRNA decay by recognizing METTL3-mediated m(6)A modification to activate NF-κB and promote the malignant progression of glioma
title YTHDF2 facilitates UBXN1 mRNA decay by recognizing METTL3-mediated m(6)A modification to activate NF-κB and promote the malignant progression of glioma
title_full YTHDF2 facilitates UBXN1 mRNA decay by recognizing METTL3-mediated m(6)A modification to activate NF-κB and promote the malignant progression of glioma
title_fullStr YTHDF2 facilitates UBXN1 mRNA decay by recognizing METTL3-mediated m(6)A modification to activate NF-κB and promote the malignant progression of glioma
title_full_unstemmed YTHDF2 facilitates UBXN1 mRNA decay by recognizing METTL3-mediated m(6)A modification to activate NF-κB and promote the malignant progression of glioma
title_short YTHDF2 facilitates UBXN1 mRNA decay by recognizing METTL3-mediated m(6)A modification to activate NF-κB and promote the malignant progression of glioma
title_sort ythdf2 facilitates ubxn1 mrna decay by recognizing mettl3-mediated m(6)a modification to activate nf-κb and promote the malignant progression of glioma
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8272379/
https://www.ncbi.nlm.nih.gov/pubmed/34246306
http://dx.doi.org/10.1186/s13045-021-01124-z
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