A Druggable UHRF1/DNMT1/GLI Complex Regulates Sonic Hedgehog-Dependent Tumor Growth

Area of Science:

• Oncology
• Molecular Biology
• Epigenetics

Background:

• Sonic hedgehog (SHH) signaling pathway dysregulation is a key driver in various cancers, notably medulloblastoma (MB).
• Current therapies targeting SHH signaling, primarily Smoothened (SMO) inhibitors, face challenges due to acquired drug resistance, often caused by SMO mutations.
• The need for novel therapeutic strategies targeting components downstream of SMO is critical for overcoming resistance in SHH-driven cancers.

Purpose of the Study:

• To identify novel epigenetic regulators of the SHH signaling pathway.
• To investigate a newly identified complex involving Ubiquitin-like with PHD and RING finger domains 1 (UHRF1), DNA methyltransferase 1 (DNMT1), and GLI proteins.
• To evaluate the therapeutic potential of targeting this complex in SHH-dependent tumors, particularly in the context of SMO inhibitor resistance.

Main Methods:

• Integrated functional genomics approach to identify epigenetic regulators of SHH signaling.
• Biochemical and cellular assays to characterize the novel UHRF1/DNMT1/GLI complex.
• Ex vivo and in vivo studies using medulloblastoma models to assess the efficacy of a repurposed FDA-approved therapy targeting the complex.

Main Results:

• Identification of a novel UHRF1/DNMT1/GLI complex distinct from previously described UHRF1/DNMT1 interactions.
• Demonstration that this complex plays a crucial role in regulating GLI activity within SHH-driven tumors.
• Confirmation that targeting the stability of the UHRF1/DNMT1/GLI complex with a repurposed FDA-approved drug significantly reduces SHH-dependent medulloblastoma growth both ex vivo and in vivo.

Conclusions:

• A novel, druggable UHRF1/DNMT1/GLI complex is identified as a key regulator of SHH-dependent tumor growth.
• This complex represents a promising therapeutic target for SHH-driven cancers, including medulloblastoma.
• Repurposing an FDA-approved drug to disrupt the UHRF1/DNMT1/GLI complex offers a viable strategy to overcome SMO inhibitor resistance and attenuate tumor progression.