Epigenetic targeting of Hedgehog pathway transcriptional output through BET bromodomain inhibition.

Nat Med
Authors
Keywords
Abstract

Hedgehog signaling drives oncogenesis in several cancers, and strategies targeting this pathway have been developed, most notably through inhibition of Smoothened (SMO). However, resistance to Smoothened inhibitors occurs by genetic changes of Smoothened or other downstream Hedgehog components. Here we overcome these resistance mechanisms by modulating GLI transcription through inhibition of bromo and extra C-terminal (BET) bromodomain proteins. We show that BRD4 and other BET bromodomain proteins regulate GLI transcription downstream of SMO and suppressor of fused (SUFU), and chromatin immunoprecipitation studies reveal that BRD4 directly occupies GLI1 and GLI2 promoters, with a substantial decrease in engagement of these sites after treatment with JQ1, a small-molecule inhibitor targeting BRD4. Globally, genes associated with medulloblastoma-specific GLI1 binding sites are downregulated in response to JQ1 treatment, supporting direct regulation of GLI activity by BRD4. Notably, patient- and GEMM (genetically engineered mouse model)-derived Hedgehog-driven tumors (basal cell carcinoma, medulloblastoma and atypical teratoid rhabdoid tumor) respond to JQ1 even when harboring genetic lesions rendering them resistant to Smoothened antagonists. Altogether, our results reveal BET proteins as critical regulators of Hedgehog pathway transcriptional output and nominate BET bromodomain inhibitors as a strategy for treating Hedgehog-driven tumors with emerged or a priori resistance to Smoothened antagonists.

Year of Publication
2014
Journal
Nat Med
Volume
20
Issue
7
Pages
732-40
Date Published
2014 Jul
ISSN
1546-170X
URL
DOI
10.1038/nm.3613
PubMed ID
24973920
PubMed Central ID
PMC4108909
Links
Grant list
U01 CA176287 / CA / NCI NIH HHS / United States
R01 EY014167 / EY / NEI NIH HHS / United States
U01-CA176287 / CA / NCI NIH HHS / United States
R01 CA159859 / CA / NCI NIH HHS / United States
R01 EY016060 / EY / NEI NIH HHS / United States
R01-CA159859 / CA / NCI NIH HHS / United States
R01 AR046786 / AR / NIAMS NIH HHS / United States
R01 CA157895 / CA / NCI NIH HHS / United States
P30 CA124435 / CA / NCI NIH HHS / United States
P30 EY001931 / EY / NEI NIH HHS / United States