ZRANB1 depletion inhibits neuroblastoma progression by destabilizing MYCN through EZH2-mediated deubiquitination.
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BACKGROUND: Neuroblastoma (NB) is a common malignant solid tumor in children, notably aggressive in cases with MYCN amplification. Unraveling the mechanisms behind NB progression is crucial for developing targeted therapies. ZRANB1, a deubiquitinating enzyme, has emerged as a significant player in many cancers, but its specific function in NB still to be fully elucidated. METHODS: Bioinformatic analyses of transcriptomic datasets (GSE85047 and GSE80149) were performed to identify potential MYCN-dependent pro-survival genes. The biological functions of ZRANB1 in NB cells were assessed by CCK-8, colony formation, migration, invasion, and tumor sphere formation assays. Co-IP, Western blot, CHX chase, and ubiquitination assays were performed to assess the regulatory relationship among ZRANB1, EZH2, and MYCN. Catalytically inactive ZRANB1 mutant and in vitro pull-down assays were performed to validate the requirement of deubiquitinase activity and direct interactions. We evaluated the contribution of the ZRANB1-EZH2-MYCN axis to tumor growth using cell-based assays and mouse xenograft models. RESULTS: ZARNB1 was substantially higher in MYCN-amplified BE(2)M17 cell lines. Functional studies demonstrated that ZRANB1 promoted proliferation, migration, and tumorigenicity. Mechanistically, although ZRANB1 did not directly bind MYCN, it formed a ternary complex with EZH2 and MYCN, thereby stabilizing MYCN via EZH2-mediated regulation. Deubiquitinase activity was required for ZRANB1-mediated MYCN stabilization, and direct ZRANB1-EZH2 interaction was confirmed by in vitro pull-down assays. CONCLUSIONS: This study identifies ZRANB1 as an upstream deubiquitinase that stabilizes EZH2, thereby indirectly maintaining MYCN stability in MYCN-amplified neuroblastoma. These findings establish a ZRANB1-EZH2-MYCN regulatory axis and highlight ZRANB1 as a promising therapeutic target in MYCN-amplified NB.