Abstract Background Group 3 medulloblastoma (G3 MB) is the most aggressive medulloblastoma subtype, with high relapse rates and limited curative options. We previously identified lnc-HLX-2-7 as a G3 MB–specific oncogenic lncRNA sustaining a lnc-HLX-2-7–HLX–MYC circuit. Here, we define the functional role of the RNA-binding protein YBX1 within this axis and evaluate its therapeutic tractability. Methods Molecular partners of lnc-HLX-2-7 were identified using RNA immunoprecipitation (RIP), confirming YBX1 as a direct interacting protein in G3 MB cells. The functional role of YBX1 was investigated using stable genetic knockdown and the small-molecule inhibitor SU056. Antitumor effects were evaluated using in vitro assays assessing cell proliferation, clonogenic capacity, and apoptosis (caspase activity), as well as in vivo orthotopic intracranial xenografts from G3 MB cell lines D425 and D283, with evaluation of tumor growth kinetics and overall survival. In parallel, changes in HLX and MYC expression were quantified by qPCR following YBX1 knockdown or inhibition and after lnc-HLX-2-7 depletion Results RIP demonstrated a specific interaction between lnc-HLX-2-7 and YBX1 in G3 MB cells. Genetic depletion of YBX1 markedly impaired proliferation and tumorigenicity, accompanied by reduced HLX and MYC expression and the suppression of oncogenic and metabolic programs. Depletion of lnc-HLX-2-7 similarly lowered HLX and MYC, supporting a lnc-HLX-2-7–dependent role for YBX1 in maintaining this axis. Consistent with genetic loss, pharmacologic YBX1 inhibition with SU056 significantly suppressed G3 MB growth in vitro and in intracranial xenografts, and prolonged overall survival in mice bearing D425 and D283 tumors. In vitro, SU056 increased caspase activity, indicating induction of apoptosis. Conclusions YBX1 is a central effector of G3 MB biology operating within an lnc-HLX-2-7–HLX–MYC pathway. Targeting YBX1 with SU056 induces apoptosis in vitro and extends survival in preclinical models, highlighting YBX1 as a promising therapeutic vulnerability for this high-risk pediatric brain tumor.
Sanada et al. (Tue,) studied this question.