Targeting histone deacetylase suppresses tumor growth through eliciting METTL14‐modified m6A RNA methylation in ocular melanoma
Abstract Background Diversified histone deacetylation inhibitors (HDACis) have demonstrated encouraging outcomes in multiple malignancies. N6‐methyladenine (m6A) is the most prevalent messenger RNA modification that plays an essential role in the regulation of tumorigenesis. Howbeit, an in‐depth und...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-11-01
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| Series: | Cancer Communications |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/cac2.12471 |
| _version_ | 1797633634367176704 |
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| author | Ai Zhuang Xiang Gu Tongxin Ge Shaoyun Wang Shengfang Ge Peiwei Chai Renbing Jia Xianqun Fan |
| author_facet | Ai Zhuang Xiang Gu Tongxin Ge Shaoyun Wang Shengfang Ge Peiwei Chai Renbing Jia Xianqun Fan |
| author_sort | Ai Zhuang |
| collection | DOAJ |
| description | Abstract Background Diversified histone deacetylation inhibitors (HDACis) have demonstrated encouraging outcomes in multiple malignancies. N6‐methyladenine (m6A) 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 m6A RNA modifications remains enigmatic. This study aimed to explore the role of histone acetylation and m6A 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 m6A RNA modification level. Multi‐omics assays, including RNA‐sequencing, cleavage under targets and tagmentation, single‐cell sequencing, methylated RNA immunoprecipitation‐sequencing (meRIP‐seq), and m6A 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 m6A levels of FAT4 were affected. Results First, we found that ocular melanoma cells presented vulnerability towards HDACis. HDACis triggered the elevation of m6A 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 m6A‐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 m6A modification in tumorigenesis. Conclusions These results demonstrate that HDACis exert anti‐cancer effects by orchestrating m6A modification, which unveiling a “histone‐RNA crosstalk” of the HDAC/METTL14/FAT4 epigenetic cascade in ocular melanoma. |
| first_indexed | 2024-03-11T11:56:39Z |
| format | Article |
| id | doaj.art-4ac9993639d944488fddab79b4e4859c |
| institution | Directory Open Access Journal |
| issn | 2523-3548 |
| language | English |
| last_indexed | 2024-03-11T11:56:39Z |
| publishDate | 2023-11-01 |
| publisher | Wiley |
| record_format | Article |
| series | Cancer Communications |
| spelling | doaj.art-4ac9993639d944488fddab79b4e4859c2023-11-08T15:31:49ZengWileyCancer Communications2523-35482023-11-0143111185120610.1002/cac2.12471Targeting histone deacetylase suppresses tumor growth through eliciting METTL14‐modified m6A RNA methylation in ocular melanomaAi Zhuang0Xiang Gu1Tongxin Ge2Shaoyun Wang3Shengfang Ge4Peiwei Chai5Renbing Jia6Xianqun Fan7Department of Ophthalmology Shanghai Ninth People's Hospital Shanghai JiaoTong University School of Medicine Shanghai P. R. ChinaDepartment of Ophthalmology Shanghai Ninth People's Hospital Shanghai JiaoTong University School of Medicine Shanghai P. R. ChinaDepartment of Ophthalmology Shanghai Ninth People's Hospital Shanghai JiaoTong University School of Medicine Shanghai P. R. ChinaDepartment of Ophthalmology Shanghai Ninth People's Hospital Shanghai JiaoTong University School of Medicine Shanghai P. R. ChinaDepartment of Ophthalmology Shanghai Ninth People's Hospital Shanghai JiaoTong University School of Medicine Shanghai P. R. ChinaDepartment of Ophthalmology Shanghai Ninth People's Hospital Shanghai JiaoTong University School of Medicine Shanghai P. R. ChinaDepartment of Ophthalmology Shanghai Ninth People's Hospital Shanghai JiaoTong University School of Medicine Shanghai P. R. ChinaDepartment of Ophthalmology Shanghai Ninth People's Hospital Shanghai JiaoTong University School of Medicine Shanghai P. R. ChinaAbstract Background Diversified histone deacetylation inhibitors (HDACis) have demonstrated encouraging outcomes in multiple malignancies. N6‐methyladenine (m6A) 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 m6A RNA modifications remains enigmatic. This study aimed to explore the role of histone acetylation and m6A 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 m6A RNA modification level. Multi‐omics assays, including RNA‐sequencing, cleavage under targets and tagmentation, single‐cell sequencing, methylated RNA immunoprecipitation‐sequencing (meRIP‐seq), and m6A 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 m6A levels of FAT4 were affected. Results First, we found that ocular melanoma cells presented vulnerability towards HDACis. HDACis triggered the elevation of m6A 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 m6A‐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 m6A modification in tumorigenesis. Conclusions These results demonstrate that HDACis exert anti‐cancer effects by orchestrating m6A modification, which unveiling a “histone‐RNA crosstalk” of the HDAC/METTL14/FAT4 epigenetic cascade in ocular melanoma.https://doi.org/10.1002/cac2.12471epigeneticshistone deacetylation inhibitorsmelanomaN6‐methyladeninehistone‐RNA crosstalk |
| spellingShingle | Ai Zhuang Xiang Gu Tongxin Ge Shaoyun Wang Shengfang Ge Peiwei Chai Renbing Jia Xianqun Fan Targeting histone deacetylase suppresses tumor growth through eliciting METTL14‐modified m6A RNA methylation in ocular melanoma Cancer Communications epigenetics histone deacetylation inhibitors melanoma N6‐methyladenine histone‐RNA crosstalk |
| title | Targeting histone deacetylase suppresses tumor growth through eliciting METTL14‐modified m6A RNA methylation in ocular melanoma |
| title_full | Targeting histone deacetylase suppresses tumor growth through eliciting METTL14‐modified m6A RNA methylation in ocular melanoma |
| title_fullStr | Targeting histone deacetylase suppresses tumor growth through eliciting METTL14‐modified m6A RNA methylation in ocular melanoma |
| title_full_unstemmed | Targeting histone deacetylase suppresses tumor growth through eliciting METTL14‐modified m6A RNA methylation in ocular melanoma |
| title_short | Targeting histone deacetylase suppresses tumor growth through eliciting METTL14‐modified m6A RNA methylation in ocular melanoma |
| title_sort | targeting histone deacetylase suppresses tumor growth through eliciting mettl14 modified m6a rna methylation in ocular melanoma |
| topic | epigenetics histone deacetylation inhibitors melanoma N6‐methyladenine histone‐RNA crosstalk |
| url | https://doi.org/10.1002/cac2.12471 |
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