iProXProteomicsJiayan FanHomo Sapienshttp://www.iprox.org/page/project.html?id=IPX0009100000qingyang@sjtu.edu.cnShanghai Jiao Tong UniversityiProXfalseMYCN-mediates ferroptosis escape in accelerates tumorigenesis via UBE2CMYCN is a common oncogenic alteration in tumors, representing one of the high-risk molecular subtypes of tumors. However, the functional role of MYCN in tumorigenesis remains to be elucidated. Here, we report that MYCN binds to the UBE2C promoter and upregulates its transcription, accelerating the progression of neuroectodermal tumor. The proteomic analysis of UBE2C-interacting proteins revealed TFRC, a well-known tumor suppressor, is a novel ubiquitin target of UBE2C. Subsequently, immunoprecipitation assay demonstrates UBE2C downregulate TFRC expression via ubiquitinoylation in neuroectodermal tumor. Suppression of UBE2C in tumor cells induced ferroptosis and increased sensitivity to the ferroptosis inducer erastin. Taken together, our findings reveal a novel MYCN-UBE2C-TFRC-ferroptosis regulatory cascade in controlling MYCN activation cell proliferation and tumor growth, pinpointing an unprecedented mechanism of MYCN-mediated evasion of ferroptosis escape in tumor. This study provides useful insights into the theoretical underpinning for therapy of MYCN activation tumors.Sun Jun 23 00:00:00 BST 2024PXD0533449606