NEDD8-specific protease 1 deficiency as a novel driver of hepatoblastoma development through dysregulation of the CAND1-NEDD8 pathway.

BACKGROUND AND AIMS: Hepatoblastoma (HB) is the most common malignant liver tumor in children. Despite advances in multimodal treatment, chemoresistance and relapses remain major clinical challenges. NEDDylation, a post-translational modification involving the ubiquitin-like molecule NEDD8, has been implicated in cancer, but its role in HB remains poorly understood. This study investigates the functional relevance of the deNEDDylase NEDP1 and its downstream target CAND1 in HB progression and therapy response.

APPROACH AND

RESULTS

Transcriptomic and proteomic analyses of HB patient samples, cell lines, patient-derived xenograft (PDX) cells, and transgenic mouse models revealed a significant reduction in NEDP1 expression and activity, accompanied by global hyper-NEDDylation. Functional studies demonstrated that NEDP1 overexpression restored deNEDDylation, induced apoptosis, impaired tumor cell proliferation and metabolism, and significantly restrained tumor growth and metastasis in both in vivo mouse models and in the chorioallantoic membrane (CAM) assay. Proteomic profiling identified CAND1 as a key NEDDylated substrate regulated by NEDP1. High CAND1 expression was associated with aggressive molecular HB subtypes (C2-pure, Epi-CB) and poor clinical outcomes, including reduced overall survival. Rescue experiments confirmed that CAND1 overexpression counteracted the antitumor effects of NEDP1.

CONCLUSIONS

NEDP1 acts as a tumor suppressor in HB by modulating the NEDDylation status of key regulatory proteins, particularly CAND1. Restoration of NEDP1 activity suppresses tumorigenesis and metastasis, underscoring the NEDDylation pathway as a promising therapeutic target. CAND1 is proposed as a potential prognostic biomarker and actionable oncogenic driver in HB.