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Targeting histone deacetylase suppresses tumor growth through eliciting METTL14‐modified m(6)A RNA methylation in ocular melanoma

BACKGROUND: Diversified histone deacetylation inhibitors (HDACis) have demonstrated encouraging outcomes in multiple malignancies. N6‐methyladenine (m(6)A) is the most prevalent messenger RNA modification that plays an essential role in the regulation of tumorigenesis. Howbeit, an in‐depth understan...

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Autores principales: Zhuang, Ai, Gu, Xiang, Ge, Tongxin, Wang, Shaoyun, Ge, Shengfang, Chai, Peiwei, Jia, Renbing, Fan, Xianqun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10631484/
https://www.ncbi.nlm.nih.gov/pubmed/37466203
http://dx.doi.org/10.1002/cac2.12471
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author Zhuang, Ai
Gu, Xiang
Ge, Tongxin
Wang, Shaoyun
Ge, Shengfang
Chai, Peiwei
Jia, Renbing
Fan, Xianqun
author_facet Zhuang, Ai
Gu, Xiang
Ge, Tongxin
Wang, Shaoyun
Ge, Shengfang
Chai, Peiwei
Jia, Renbing
Fan, Xianqun
author_sort Zhuang, Ai
collection PubMed
description BACKGROUND: Diversified histone deacetylation inhibitors (HDACis) have demonstrated encouraging outcomes in multiple malignancies. N6‐methyladenine (m(6)A) is the most prevalent messenger RNA modification that plays an essential role in the regulation of tumorigenesis. Howbeit, an in‐depth understanding of the crosstalk between histone acetylation and m(6)A RNA modifications remains enigmatic. This study aimed to explore the role of histone acetylation and m(6)A modifications in the regulation of tumorigenesis of ocular melanoma. METHODS: Histone modification inhibitor screening was used to explore the effects of HDACis on ocular melanoma cells. Dot blot assay was used to detect the global m(6)A RNA modification level. Multi‐omics assays, including RNA‐sequencing, cleavage under targets and tagmentation, single‐cell sequencing, methylated RNA immunoprecipitation‐sequencing (meRIP‐seq), and m(6)A individual nucleotide resolution cross‐linking and immunoprecipitation‐sequencing (miCLIP‐seq), were performed to reveal the mechanisms of HDACis on methyltransferase‐like 14 (METTL14) and FAT tumor suppressor homolog 4 (FAT4) in ocular melanoma. Quantitative real‐time polymerase chain reaction (qPCR), western blotting, and immunofluorescent staining were applied to detect the expression of METTL14 and FAT4 in ocular melanoma cells and tissues. Cell models and orthotopic xenograft models were established to determine the roles of METTL14 and FAT4 in the growth of ocular melanoma. RNA‐binding protein immunoprecipitation‐qPCR, meRIP‐seq, miCLIP‐seq, and RNA stability assay were adopted to investigate the mechanism by which m(6)A levels of FAT4 were affected. RESULTS: First, we found that ocular melanoma cells presented vulnerability towards HDACis. HDACis triggered the elevation of m(6)A RNA modification in ocular melanoma. Further studies revealed that METTL14 served as a downstream candidate for HDACis. METTL14 was silenced by the hypo‐histone acetylation status, whereas HDACi restored the normal histone acetylation level of METTL14, thereby inducing its expression. Subsequently, METTL14 served as a tumor suppressor by promoting the expression of FAT4, a tumor suppressor, in a m(6)A‐YTH N6‐methyladenosine RNA‐binding protein 1‐dependent manner. Taken together, we found that HDACi restored the histone acetylation level of METTL14 and subsequently elicited METTL14‐mediated m(6)A modification in tumorigenesis. CONCLUSIONS: These results demonstrate that HDACis exert anti‐cancer effects by orchestrating m(6)A modification, which unveiling a “histone‐RNA crosstalk” of the HDAC/METTL14/FAT4 epigenetic cascade in ocular melanoma.
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spelling pubmed-106314842023-11-15 Targeting histone deacetylase suppresses tumor growth through eliciting METTL14‐modified m(6)A RNA methylation in ocular melanoma Zhuang, Ai Gu, Xiang Ge, Tongxin Wang, Shaoyun Ge, Shengfang Chai, Peiwei Jia, Renbing Fan, Xianqun Cancer Commun (Lond) Original Articles BACKGROUND: Diversified histone deacetylation inhibitors (HDACis) have demonstrated encouraging outcomes in multiple malignancies. N6‐methyladenine (m(6)A) is the most prevalent messenger RNA modification that plays an essential role in the regulation of tumorigenesis. Howbeit, an in‐depth understanding of the crosstalk between histone acetylation and m(6)A RNA modifications remains enigmatic. This study aimed to explore the role of histone acetylation and m(6)A modifications in the regulation of tumorigenesis of ocular melanoma. METHODS: Histone modification inhibitor screening was used to explore the effects of HDACis on ocular melanoma cells. Dot blot assay was used to detect the global m(6)A RNA modification level. Multi‐omics assays, including RNA‐sequencing, cleavage under targets and tagmentation, single‐cell sequencing, methylated RNA immunoprecipitation‐sequencing (meRIP‐seq), and m(6)A individual nucleotide resolution cross‐linking and immunoprecipitation‐sequencing (miCLIP‐seq), were performed to reveal the mechanisms of HDACis on methyltransferase‐like 14 (METTL14) and FAT tumor suppressor homolog 4 (FAT4) in ocular melanoma. Quantitative real‐time polymerase chain reaction (qPCR), western blotting, and immunofluorescent staining were applied to detect the expression of METTL14 and FAT4 in ocular melanoma cells and tissues. Cell models and orthotopic xenograft models were established to determine the roles of METTL14 and FAT4 in the growth of ocular melanoma. RNA‐binding protein immunoprecipitation‐qPCR, meRIP‐seq, miCLIP‐seq, and RNA stability assay were adopted to investigate the mechanism by which m(6)A levels of FAT4 were affected. RESULTS: First, we found that ocular melanoma cells presented vulnerability towards HDACis. HDACis triggered the elevation of m(6)A RNA modification in ocular melanoma. Further studies revealed that METTL14 served as a downstream candidate for HDACis. METTL14 was silenced by the hypo‐histone acetylation status, whereas HDACi restored the normal histone acetylation level of METTL14, thereby inducing its expression. Subsequently, METTL14 served as a tumor suppressor by promoting the expression of FAT4, a tumor suppressor, in a m(6)A‐YTH N6‐methyladenosine RNA‐binding protein 1‐dependent manner. Taken together, we found that HDACi restored the histone acetylation level of METTL14 and subsequently elicited METTL14‐mediated m(6)A modification in tumorigenesis. CONCLUSIONS: These results demonstrate that HDACis exert anti‐cancer effects by orchestrating m(6)A modification, which unveiling a “histone‐RNA crosstalk” of the HDAC/METTL14/FAT4 epigenetic cascade in ocular melanoma. John Wiley and Sons Inc. 2023-07-19 /pmc/articles/PMC10631484/ /pubmed/37466203 http://dx.doi.org/10.1002/cac2.12471 Text en © 2023 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat‐sen University Cancer Center. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Articles
Zhuang, Ai
Gu, Xiang
Ge, Tongxin
Wang, Shaoyun
Ge, Shengfang
Chai, Peiwei
Jia, Renbing
Fan, Xianqun
Targeting histone deacetylase suppresses tumor growth through eliciting METTL14‐modified m(6)A RNA methylation in ocular melanoma
title Targeting histone deacetylase suppresses tumor growth through eliciting METTL14‐modified m(6)A RNA methylation in ocular melanoma
title_full Targeting histone deacetylase suppresses tumor growth through eliciting METTL14‐modified m(6)A RNA methylation in ocular melanoma
title_fullStr Targeting histone deacetylase suppresses tumor growth through eliciting METTL14‐modified m(6)A RNA methylation in ocular melanoma
title_full_unstemmed Targeting histone deacetylase suppresses tumor growth through eliciting METTL14‐modified m(6)A RNA methylation in ocular melanoma
title_short Targeting histone deacetylase suppresses tumor growth through eliciting METTL14‐modified m(6)A RNA methylation in ocular melanoma
title_sort targeting histone deacetylase suppresses tumor growth through eliciting mettl14‐modified m(6)a rna methylation in ocular melanoma
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10631484/
https://www.ncbi.nlm.nih.gov/pubmed/37466203
http://dx.doi.org/10.1002/cac2.12471
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