Super-enhancer-driven USP36 promotes glycolytic reprogramming and neuroblastoma progression by stabilizing DHX33

ABSTRACT: Neuroblastoma (NB) is the most common extracranial solid tumor in children and is characterized by pronounced glycolytic metabolism and a poor clinical prognosis. However, its core pathogenic mechanisms and effective therapeutic targets remain incompletely understood. This study identifies ubiquitin-specific protease USP36 as a critical regulator in NB pathogenesis. We demonstrate that USP36 expression is significantly elevated in NB tissues and cell lines compared with other tumor types, and high USP36 expression strongly correlates with adverse patient outcomes. Mechanistically, USP36 transcription is directly driven by a super-enhancer (SE), establishing USP36 as a key SE-dependent deubiquitinating enzyme in NB. Functional analyses reveal that USP36 knockdown markedly suppresses NB cell proliferation and tumor progression both in vitro and in vivo. Transcriptomic profiling further shows that USP36 silencing induces broad downregulation of glycolysis- and hypoxia-response-related pathways and significantly impairs glycolytic flux in NB cells. At the molecular level, co-immunoprecipitation coupled with mass spectrometry identifies the RNA helicase DHX33 as a bona fide substrate of USP36. USP36 specifically removes K48-linked polyubiquitin chains from DHX33, thereby inhibiting its proteasomal degradation and enhancing its protein stability. Through small-molecule virtual screening, we identify Adavivint as a promising USP36 inhibitor; low-dose Adavivint treatment effectively reduces USP36 expression and robustly suppresses NB cell proliferation both in vitro and in vivo. Moreover, we observe that endogenous USP36 undergoes liquid–liquid phase separation (LLPS) in NB cells, suggesting a potential role for USP36 condensates in transcriptional regulation. Collectively, this study uncovers a super-enhancer-driven USP36–DHX33 signaling axis that promotes NB progression by coordinately regulating glycolytic metabolism and hypoxia adaptation, and highlights the translational potential of USP36 as both a prognostic biomarker and a therapeutic target.

ORGANISM(S): Homo sapiens

PROVIDER: GSE346164 | GEO | 2026/09/09

REPOSITORIES: GEO