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However, it is unknown if m<jats:sup>6<\/jats:sup>A RNA methylation affects uveal melanoma (UM) development. To address this question, we probed its function and molecular mechanism in UM. Initially, we demonstrated that global RNA m<jats:sup>6<\/jats:sup>A methylation levels were dramatically elevated in both UM cell lines and clinical specimens. Meanwhile, we found that METTL3, a main m<jats:sup>6<\/jats:sup>A regulatory enzyme, was significantly increased in UM cells and specimens. Subsequently, cycloleucine (Cyc) or METTL3 targeted small interfering RNA was used to block m<jats:sup>6<\/jats:sup>A methylation in UM cells. We found that Cyc or silencing METTL3 significantly suppressed UM cell proliferation and colony formation through cell cycle G1 arrest, as well as migration and invasion by functional analysis. On the other hand, overexpression of METTL3 had the opposite effects. Furthermore, bioinformatics and methylated RNA immunoprecipitation\u2010quantitative polymerase chain reaction identified <jats:italic>c\u2010Met<\/jats:italic> as a direct target of m<jats:sup>6<\/jats:sup>A methylation in UM cells. In addition, western blot analysis showed that Cyc or knockdown of METTL3 downregulated c\u2010Met, p\u2010Akt, and cell cycle\u2010related protein levels in UM cells. Taken together, our results demonstrate that METTL3\u2010mediated m<jats:sup>6<\/jats:sup>A RNA methylation modulates UM cell proliferation, migration, and invasion by targeting c\u2010Met. Such a modification acts as a critical oncogenic regulator in UM development.<\/jats:p>","DOI":"10.1002\/jcp.29608","type":"journal-article","created":{"date-parts":[[2020,2,4]],"date-time":"2020-02-04T11:26:22Z","timestamp":1580815582000},"page":"7107-7119","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":56,"title":["RNA m<sup>6<\/sup>A methylation regulates uveal melanoma cell proliferation, migration, and invasion by targeting c\u2010Met"],"prefix":"10.1002","volume":"235","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1400-2130","authenticated-orcid":false,"given":"Guangying","family":"Luo","sequence":"first","affiliation":[{"name":"School of Ophthalmology and Optometry, Eye Hospital Wenzhou Medical University Wenzhou Zhejiang China"},{"name":"State Key Laboratory of Ophthalmology Optometry and Visual Science Wenzhou Zhejiang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weiwei","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Ophthalmology and Optometry, Eye Hospital Wenzhou Medical University Wenzhou Zhejiang China"},{"name":"State Key Laboratory of Ophthalmology Optometry and Visual Science Wenzhou Zhejiang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yunping","family":"Zhao","sequence":"additional","affiliation":[{"name":"School of Ophthalmology and Optometry, Eye Hospital Wenzhou Medical University Wenzhou Zhejiang China"},{"name":"State Key Laboratory of Ophthalmology Optometry and Visual Science Wenzhou Zhejiang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shanshan","family":"Jin","sequence":"additional","affiliation":[{"name":"School of Ophthalmology and Optometry, Eye Hospital Wenzhou Medical University Wenzhou Zhejiang China"},{"name":"State Key Laboratory of Ophthalmology Optometry and Visual Science Wenzhou Zhejiang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Siqi","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Ophthalmology and Optometry, Eye Hospital Wenzhou Medical University Wenzhou Zhejiang China"},{"name":"State Key Laboratory of Ophthalmology Optometry and Visual Science Wenzhou Zhejiang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qi","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Ophthalmology and Optometry, Eye Hospital Wenzhou Medical University Wenzhou Zhejiang China"},{"name":"State Key Laboratory of Ophthalmology Optometry and Visual Science Wenzhou Zhejiang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoyan","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Ophthalmology and Optometry, Eye Hospital Wenzhou Medical University Wenzhou Zhejiang China"},{"name":"State Key Laboratory of Ophthalmology Optometry and Visual Science Wenzhou Zhejiang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiao","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Ophthalmology and Optometry, Eye Hospital Wenzhou Medical University Wenzhou Zhejiang China"},{"name":"State Key Laboratory of Ophthalmology Optometry and Visual Science Wenzhou Zhejiang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Feng","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, The First Affiliated Hospital of School of Medicine Zhejiang University Hangzhou Zhejiang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dan\u2010Ning","family":"Hu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology Optometry and Visual Science Wenzhou Zhejiang China"},{"name":"Tissue Culture Center, The New York Eye and Ear Infirmary New York Medical College New York New York"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter S.","family":"Reinach","sequence":"additional","affiliation":[{"name":"School of Ophthalmology and Optometry, Eye Hospital Wenzhou Medical University Wenzhou Zhejiang China"},{"name":"State Key Laboratory of Ophthalmology Optometry and Visual Science Wenzhou Zhejiang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0551-2219","authenticated-orcid":false,"given":"Dongsheng","family":"Yan","sequence":"additional","affiliation":[{"name":"School of Ophthalmology and Optometry, Eye Hospital Wenzhou Medical University Wenzhou Zhejiang China"},{"name":"State Key Laboratory of Ophthalmology Optometry and Visual Science Wenzhou Zhejiang China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2020,2,4]]},"reference":[{"issue":"8","key":"e_1_2_9_2_1","first-page":"4811","article-title":"Uveal melanoma: 5 Year update on incidence, treatment, and survival (SEER 1973\u20132013)","volume":"58","author":"Aronow M. 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