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

Dysregulation of Sonic hedgehog (SHH) signaling drives the growth of distinct cancer subtypes, including medulloblastoma (MB). Such cancers have been treated in the clinic with a number of clinically relevant SHH inhibitors, the majority of which target the upstream SHH regulator, Smoothened (SMO). Despite consid-erable efficacy, many of these patients develop resistance to these drugs, primarily due to mutations in SMO. Therefore, it is essential to identify druggable, signaling components downstream of SMO to target in SMO inhibitor resistant cancers. We utilized an integrated functional genomics approach to identify epigenetic regulators of SHH signaling and identified a novel complex of Ubiquitin-like with PHD and RING finger domains 1 (UHRF1), DNA methyltransfer-ase 1 (DNMT1), and GLI proteins. We show that this complex is distinct from previously described UHRF1/DNMT1 complexes, suggesting that it works in concert to regulate GLI activity in SHH driven tumors. Importantly, we show that UHRF1/DNMT1/GLI complex stability is targeted by a repurposed FDA-approved ther-apy, with a subsequent reduction in the growth of SHH-dependent MB ex vivo and in vivo.Implications: This work describes a novel, druggable UHRF1/ DNMT1/GLI complex that regulates SHH-dependent tumor growth, and highlights an FDA-approved drug capable of disrupt-ing this complex to attenuate tumor growth.

Automated summary

Dysregulation of SHH signaling contributes to the growth of cancer subtypes, and resistance to current SHH inhibitors is a common issue. A novel UHRF1/DNMT1/GLI complex has been identified as a potential target for regulating SHH-dependent tumor growth, with an FDA-approved drug capable of disrupting this complex to attenuate tumor growth.