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

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.