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

Oncogene volume 41, pages 1281–1297 (2022)Cite this article

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Abstract

N6-methyladenosine (m6A) is the most universal internal RNA modification on messenger RNAs and regulates the fate and functions of m6A-modified transcripts through m6A-specific binding proteins. Nevertheless, the functional role and potential mechanism of the m6A reading proteins in ocular melanoma tumorigenicity, especially cancer stem-like cell (CSC) properties, remain to be elucidated. Herein, we demonstrated that the m6A reading protein YTHDF3 promotes the translation of the target transcript CTNNB1, contributing to ocular melanoma propagation and migration through m6A 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 m6A peaks and YTHDF3 binding peaks on mRNAs revealed a key target gene candidate, CTNNB1. Mechanistically, YTHDF3 enhances CTNNB1 translation through recognizing and binding the m6A peaks on CTNNB1 mRNA.

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Fig. 1: m6A reading protein YTHDF3 is highly expressed in ocular melanoma CSCs and predicts poor survival in UVM patients.
Fig. 2: YTHDF3 is required for the tumorigenic capacity of cancer stem-like cells in ocular melanoma.
Fig. 3: YTHDF3 knockdown inhibits the proliferation and migration of ocular melanoma cells.
Fig. 4: Identification of potential downstream target genes of YTHDF3 by multiomics analysis.
Fig. 5: Expression of β-catenin is regulated by YTHDF3.
Fig. 6: CTNNB1 may serve as the key candidate gene of YTHDF3.
Fig. 7: YTHDF3 regulates CTNNB1 expression by facilitating the translation process in an m6A-dependent manner.

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Data availability

The raw sequencing data supporting the conclusions of this paper, including RNA-seq, miCLIP-seq, and iCLIP-seq data, have been deposited in the Genome Sequence Archive [65] in the BIG Data Center [66], Beijing Institute of Genomics (BIG), Chinese Academy of Sciences, under accession number CRA002956 (http://bigd.big.ac.cn/gsa/s/n110138p) and are publicly accessible at http://bigd.big.ac.cn/gsa.

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Acknowledgements

We express our sincere thanks for all the patients participated in our study and wish them good health. This work was supported by the National Key Research and Development Plan (2017YFE0196300), the National Natural Science Foundation of China (81772875, U1932135, 82073889), the Clinical Research Plan of SHDC (SHDC2020CR1009A), the Science and Technology Commission of Shanghai (20DZ2270800 and 19JC1410200).

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  1. These authors contributed equally: Yangfan Xu, Xiaoyu He, Shanzheng Wang.

Authors and Affiliations

  1. Department of Ophthalmology, Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, P.R. China

    Yangfan Xu, Xiaoyu He, Ruobing Jia, Peiwei Chai, Fang Li, Shengfang Ge, Renbing Jia & Xianqun Fan

  2. Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, P.R. China

    Yangfan Xu, Xiaoyu He, Ruobing Jia, Peiwei Chai, Fang Li, Shengfang Ge, Renbing Jia & Xianqun Fan

  3. Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, P.R. China

    Shanzheng Wang, Baofa Sun, Ying Yang & Yun-Gui Yang

  4. China National Center for Bioinformation, Beijing, P.R. China

    Shanzheng Wang, Baofa Sun, Ying Yang & Yun-Gui Yang

  5. Sino-Danish College, University of Chinese Academy of Sciences, Beijing, P.R. China

    Shanzheng Wang, Baofa Sun, Ying Yang & Yun-Gui Yang

  6. Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, P.R. China

    Baofa Sun, Ying Yang & Yun-Gui Yang

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Contributions

XQF and YGY designed the research, supervised the experiments and approved the paper. YFX and XYH performed the experiments with assistance from RBJ, PWC, FL, and YY; SZW and BFS performed the bioinformatics analyses and contributed to the experimental candidate selection; YFX, XYH, and SZW analyzed the data, and drafted the paper. SFG and RBJ was responsible for sample collection. All of the authors read and approved this paper.

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Correspondence to Yun-Gui Yang or Xianqun Fan.

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Written informed consent was obtained from all patients enrolled in this study. The animal research was approved by the Shanghai Jiao Tong University School of Medicine Animal Care and Use Committee.

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Xu, Y., He, X., Wang, S. et al. The m6A reading protein YTHDF3 potentiates tumorigenicity of cancer stem-like cells in ocular melanoma through facilitating CTNNB1 translation. Oncogene 41, 1281–1297 (2022). https://doi.org/10.1038/s41388-021-02146-0

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