PRR11 as a newly identified oncogenic driver in retinoblastoma

Retinoblastoma (RB) is the most common pediatric intraocular malignancy and seriously threatens vision and survival if not treated early. However, effective targeted therapies remain unavailable owing to the lack of well-defined molecular targets beyond RB1 gene mutations. There is a critical need to identify novel therapeutic targets. Through transcriptomic analysis of four RB-related datasets (GSE125903, GSE110811, GSE97508, and GSE24673) from the Gene Expression Omnibus (GEO) database, we identified proline-rich 11 (PRR11) as a significantly overexpressed gene in RB. Single-cell transcriptomic analysis revealed that PRR11 exhibits heterogeneous expression in different RB cell types, at particularly high levels in tumor-related populations such as cone precursor-like cells and MKI67⁺ photoreceptorness-decreased cells. Functional studies demonstrated that PRR11 promotes RB cell proliferation and tumor growth both in vitro and in vivo. Coimmunoprecipitation mass spectrometry (co-IP/MS) revealed that OTUB1, a deubiquitinase, interacts with and stabilizes PRR11, sustaining its high expression in RB cells. The proteomic analysis further revealed that Dickkopf WNT signaling pathway inhibitor 3 (DKK3) is a downstream adaptor downregulated by PRR11. Suppression of DKK3 by PRR11 leads to aberrant activation of the Wnt/β-catenin signaling pathway, thereby upregulating cyclin D1 and promoting S/G2M cell cycle progression. These findings establish PRR11 as an oncogenic driver in RB and highlight the OTUB1-PRR11-DKK3 axis as a regulatory mechanism of Wnt/β-catenin signaling in RB tumorigenesis. Targeting PRR11 and its downstream pathways provides a potential and novel therapeutic strategy for RB treatment.