The m6A reading protein YTHDF3 potentiates tumorigenicity of cancer stem-like cells in ocular melanoma through facilitating CTNNB1 translation

N 6 -methyladenosine (m 6 A) is the most universal internal RNA modification on messenger RNAs and regulates the fate and functions of m 6 A-modified transcripts through m 6 A-specific binding proteins. Nevertheless, the functional role and potential mechanism of the m 6 A reading proteins in ocular...

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Veröffentlicht in:Oncogene 2022-02, Vol.41 (9), p.1281-1297
Hauptverfasser: Xu, Yangfan, He, Xiaoyu, Wang, Shanzheng, Sun, Baofa, Jia, Ruobing, Chai, Peiwei, Li, Fang, Yang, Ying, Ge, Shengfang, Jia, Renbing, Yang, Yun-Gui, Fan, Xianqun
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Sprache:eng
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Zusammenfassung:N 6 -methyladenosine (m 6 A) is the most universal internal RNA modification on messenger RNAs and regulates the fate and functions of m 6 A-modified transcripts through m 6 A-specific binding proteins. Nevertheless, the functional role and potential mechanism of the m 6 A reading proteins in ocular melanoma tumorigenicity, especially cancer stem-like cell (CSC) properties, remain to be elucidated. Herein, we demonstrated that the m 6 A reading protein YTHDF3 promotes the translation of the target transcript CTNNB1 , contributing to ocular melanoma propagation and migration through m 6 A methylation. YTHDF3 is highly expressed in ocular melanoma stem-like cells and abundantly enriched in ocular melanoma tissues, which is related to poor clinical prognosis. Moreover, YTHDF3 is required for the maintenance of CSC properties and tumor initiation capacity in ocular melanoma both in vitro and in vivo. Ocular melanoma cells with targeted YTHDF3 knockdown exhibited inhibitory tumor proliferation and migration abilities. Transcriptome-wide mapping of m 6 A peaks and YTHDF3 binding peaks on mRNAs revealed a key target gene candidate, CTNNB1 . Mechanistically, YTHDF3 enhances CTNNB1 translation through recognizing and binding the m 6 A peaks on CTNNB1 mRNA.
ISSN:0950-9232
1476-5594
1476-5594
DOI:10.1038/s41388-021-02146-0