Multi-Omics Integration Identifies USP7 Inhibition as a Targetable Dependency in Neuroblastoma Through Inhibition of PRC1 Activity

Abhishek Wahi, Graduate Student

Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University

11:00 AM Eastern Time, April 17, 2026

Neuroblastoma DepMap PRC1 USP7 Multi-omics RNA-seq ChIP-seq

Abstract

Abhishek Wahi^1,2,*, Emily A. Cmarik^1,2,3, Sayali S. Chandekar^1,2, Solomon K. Otchere^1,2, Jennifer E. Sturgis^1,2, Silvi Salhotra^4,5, Allen T. Basanthakumar^4,5, Nehemiah X. Boyd¹, Giulia Digiovanni^4,5, He Zhu⁶, Gabriela Alexe^4,5,7, Daniel A. Schaefer⁴, Xing Liu⁸, Jarrod A. Marto^6,7, Sara J. Buhrlage^6,7, Kimberly Stegmaier^4,5,7,9, Nathaniel W. Mabe^1,2,3,†

1. Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University; 2. Purdue Institute for Cancer Research, Purdue University; 3. Purdue Institute for Drug Discovery; 4. Department of Pediatric Oncology, Dana-Farber Cancer Institute; 5. Broad Institute of MIT and Harvard; 6. Department of Cancer Biology, Dana-Farber Cancer Institute; 7. Harvard Medical School; 8. Department of Biochemistry, Purdue University; 9. Division of Hematology/Oncology, Boston Children's Hospital

Neuroblastoma is the most common pediatric cancer and majority of patients present high-risk disease with often dismal outcomes. It is frequently driven by genomic alterations that result in aberrant transcription factor activity and impaired differentiation during tissue development. To identify protein complex-level dependencies required for neuroblastoma, we curated a list of protein complexes using the CORUM database and mined the Dependency Map (DepMap) using single sample gene set enrichment analysis (ssGSEA). This analysis identified the non-canonical PRC1.1 complex, which represses transcriptional activity through ubiquitination of histone 2A, lysine 119 (H2AK119Ub), is a selectively enriched dependency in neuroblastoma. Knockout of several PRC1.1 subunits reduced neuroblastoma growth, arrested the cell cycle, and induced a neuronal differentiation program. While no known direct inhibitors of PRC1.1 exist, we performed co-dependency analysis of PRC1.1 subunits against all other genes in DepMap and identified that the deubiquitinase USP7 strongly correlated with PRC1.1 dependency. Treatment with USP7 inhibitor, XL177A, significantly reduced neuroblastoma growth in both cellular and animal models. Integrated multi-omics (RNA-seq,ChIP-seq, and CUT&RUN-seq) showed that both PRC1.1 knockout and USP7 inhibition resulted in highly correlated transcriptional and epigenetic alterations, suggesting that USP7 inhibition reduced neuroblastoma growth through a PRC1.1-dependent mechanism. Mechanistically, global proteomics and ubiquitinomics revealed that USP7 inhibition disrupted non-canonical PRC1 complex assembly, resulting in destabilization of PRC1.1 and subsequent proteolysis. Our findings expand our understanding of the chromatin complexes required to maintain a de-differentiated state in neuroblastoma and suggest the therapeutic potential for USP7 inhibitors in the treatment of neuroblastoma.

Bio coming soon.