A novel MYCN-YTHDF1 cascade contributes to retinoblastoma tumor growth by eliciting m^(6)A-dependent activation of multiple oncogenes  

作　　者：Yingxiu Luo Mengjia He Jie Yang Feifei Zhang Jie Chen Xuyang Wen Jiayan Fan Xianqun Fan Peiwei Chai Renbing Jia 

机构地区：[1]Department of Ophthalmology,Ninth People’s Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200011,China [2]Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology,Shanghai 200023,China

出　　处：《Science China(Life Sciences)》2023年第9期2138-2151,共14页中国科学（生命科学英文版）

基　　金：supported by the National Natural Science Foundation of China (81570884, 81872339, and 82272642);Shanghai Municipal Science and Technology Major Project (17JC1420100and 19JC1410202);Shanghai Science and Technology Development Funds (17DZ2260100 and 19QA1405100);Ninth People’s Hospital Excellent Youth Fund Program (JYYQ003)。

摘　　要：Retinoblastoma, the most prevalent primary intraocular tumor in children, leads to vision impairment, disability and even death.In addition to RB1 inactivation, MYCN activation has been documented as another common oncogenic alteration in retinoblastoma and represents one of the high-risk molecular subtypes of retinoblastoma. However, how MYCN contributes to the progression of retinoblastoma is still incompletely understood. Here, we report that MYCN upregulates YTHDF1, which encodes one of the reader proteins for N6-methyladenosine(m^(6)A) RNA modification, in retinoblastoma. We further found that this MYCN-upregulated m^(6)A reader functions to promote retinoblastoma cell proliferation and tumor growth in an m^(6)A bindingdependent manner. Mechanistically, YTHDF1 promotes the expression of multiple oncogenes by binding to their m RNAs and enhancing m RNA stability and translation in retinoblastoma cells. Taken together, our findings reveal a novel MYCN-YTHDF1regulatory cascade in controlling retinoblastoma cell proliferation and tumor growth, pinpointing an unprecedented mechanism for MYCN amplification and/or activation to promote retinoblastoma progression.

关 键 词：MYCN YTHDF1 m^(6)A CDK5R1 RETINOBLASTOMA 

分 类 号：R739.7[医药卫生—肿瘤]