1. Academic Validation
  2. m6A modification suppresses ocular melanoma through modulating HINT2 mRNA translation

m6A modification suppresses ocular melanoma through modulating HINT2 mRNA translation

  • Mol Cancer. 2019 Nov 14;18(1):161. doi: 10.1186/s12943-019-1088-x.
Ruobing Jia 1 2 Peiwei Chai 1 2 Shanzheng Wang 3 4 Baofa Sun 3 4 5 Yangfan Xu 1 2 Ying Yang 3 4 5 Shengfang Ge 1 2 Renbing Jia 6 7 Yun-Gui Yang 8 9 10 Xianqun Fan 11 12
Affiliations

Affiliations

  • 1 Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 20025, People's Republic of China.
  • 2 Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 20025, People's Republic of China.
  • 3 Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China.
  • 4 Sino-Danish College, University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 5 Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
  • 6 Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 20025, People's Republic of China. [email protected].
  • 7 Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 20025, People's Republic of China. [email protected].
  • 8 Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China. [email protected].
  • 9 Sino-Danish College, University of Chinese Academy of Sciences, Beijing, 100049, China. [email protected].
  • 10 Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China. [email protected].
  • 11 Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 20025, People's Republic of China. [email protected].
  • 12 Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 20025, People's Republic of China. [email protected].
Abstract

Background: Dynamic N6-methyladenosine (m6A) RNA modification generated and erased by N6-methyltransferases and demethylases regulates gene expression, alternative splicing and cell fate. Ocular melanoma, comprising uveal melanoma (UM) and conjunctival melanoma (CM), is the most common primary eye tumor in adults and the 2nd most common melanoma. However, the functional role of m6A modification in ocular melanoma remains unclear.

Methods: m6A assays and survival analysis were used to explore decreased global m6A levels, indicating a late stage of ocular melanoma and a poor prognosis. Multiomic analysis of miCLIP-seq, RNA-seq and Label-free MS data revealed that m6A RNA modification posttranscriptionally promoted HINT2 expression. RNA immunoprecipitation (RIP)-qPCR and dual luciferase assays revealed that HINT2 mRNA specifically interacted with YTHDF1. Furthermore, polysome profiling analysis indicated a greater amount of HINT2 mRNA in the translation pool in ocular melanoma cells with higher m6A methylation.

Results: Here, we show that RNA methylation significantly inhibits the progression of UM and CM. Ocular melanoma samples showed decreased m6A levels, indicating a poor prognosis. Changes in global m6A modification were highly associated with tumor progression in vitro and in vivo. Mechanistically, YTHDF1 promoted the translation of methylated HINT2 mRNA, a tumor suppressor in ocular melanoma.

Conclusions: Our work uncovers a critical function for m6A methylation in ocular melanoma and provides additional insight into the understanding of m6A modification.

Keywords

HINT2; Melanoma; Translation; Tumorigenesis; m6A.

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