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Inhibition of USP7 Destabilizes the Noncanonical PRC1.1 Complex and Induces Neuroblastoma Differentiation

Emily A Cmarik1,2,3, Abhishek Wahi1,2, Sayali S Chandekar1,2

  • 1Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana.

Molecular Cancer Research : MCR
|March 19, 2026
PubMed

Insights

Targeting the non-canonical PRC1.1 complex in neuroblastoma, a pediatric cancer, can induce differentiation. USP7 inhibition disrupts PRC1.1, offering a potential therapeutic strategy for neuroblastoma treatment.

Area of Science:

  • Oncology
  • Epigenetics
  • Developmental Biology

Background:

  • Pediatric cancers like neuroblastoma often stem from disrupted cellular differentiation.
  • Genomic alterations impairing differentiation are key drivers in neuroblastoma development.

Purpose of the Study:

  • To identify protein complexes crucial for differentiation in neuroblastoma.
  • To explore therapeutic strategies targeting identified dependencies.

Main Methods:

  • Utilized CORUM database for protein complexes and Dependency Map (DepMap) for gene set enrichment analysis.
  • Performed gene knockout studies, co-dependency analysis, and small molecule inhibition (USP7 inhibitor XL177A).
  • Integrated RNA-sequencing, ChIP-sequencing, global proteomics, and ubiquitinomics.

Main Results:

  • Identified the non-canonical PRC1.1 complex as a key dependency in neuroblastoma, repressing differentiation.
  • PRC1.1 subunit knockout induced neuronal differentiation and reduced tumor growth.
  • USP7 inhibition with XL177A mimicked PRC1.1 knockout effects, reducing neuroblastoma growth in vitro and in vivo.
  • USP7 inhibition disrupted PRC1.1 complex assembly, leading to its destabilization and proteolysis, reducing H2AK119Ub deposition.

Conclusions:

  • USP7 inhibition represents a promising therapeutic approach for neuroblastoma by targeting PRC1.1-mediated epigenetic repression.
  • Understanding PRC1.1 complex function is crucial for developing new treatments for neuroblastoma.
  • USP7 inhibitors can reactivate differentiation programs in neuroblastoma cells.

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