PMID- 24973920
OWN - NLM
STAT- MEDLINE
DCOM- 20140919
LR  - 20211201
IS  - 1546-170X (Electronic)
IS  - 1078-8956 (Print)
IS  - 1078-8956 (Linking)
VI  - 20
IP  - 7
DP  - 2014 Jul
TI  - Epigenetic targeting of Hedgehog pathway transcriptional output through BET 
      bromodomain inhibition.
PG  - 732-40
LID - 10.1038/nm.3613 [doi]
AB  - 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.
FAU - Tang, Yujie
AU  - Tang Y
AD  - 1] Department of Neurology and Neurological Sciences, Stanford University School 
      of Medicine, Stanford, California, USA. [2] Department of Neurosurgery, Stanford 
      University School of Medicine, Stanford, California, USA.
FAU - Gholamin, Sharareh
AU  - Gholamin S
AD  - Department of Neurosurgery, Stanford University School of Medicine, Stanford, 
      California, USA.
FAU - Schubert, Simone
AU  - Schubert S
AD  - 1] Department of Neurology and Neurological Sciences, Stanford University School 
      of Medicine, Stanford, California, USA. [2] Department of Neurosurgery, Stanford 
      University School of Medicine, Stanford, California, USA.
FAU - Willardson, Minde I
AU  - Willardson MI
AD  - Department of Cell Biology, Neurobiology and Anatomy, Medical College of 
      Wisconsin, Milwaukee, Wisconsin, USA.
FAU - Lee, Alex
AU  - Lee A
AD  - Program in Epithelial Biology, Stanford University School of Medicine, Stanford, 
      California, USA.
FAU - Bandopadhayay, Pratiti
AU  - Bandopadhayay P
AD  - 1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, 
      Massachusetts, USA. [2] Pediatric Neuro-oncology, Department of Pediatric 
      Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [3] Division 
      of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, 
      Massachusetts, USA. [4] Broad Institute of MIT and Harvard, Cambridge, 
      Massachusetts, USA.
FAU - Bergthold, Guillame
AU  - Bergthold G
AD  - 1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, 
      Massachusetts, USA. [2] Pediatric Neuro-oncology, Department of Pediatric 
      Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [3] Division 
      of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, 
      Massachusetts, USA.
FAU - Masoud, Sabran
AU  - Masoud S
AD  - Department of Neurology and Neurological Sciences, Stanford University School of 
      Medicine, Stanford, California, USA.
FAU - Nguyen, Brian
AU  - Nguyen B
AD  - Department of Neurology and Neurological Sciences, Stanford University School of 
      Medicine, Stanford, California, USA.
FAU - Vue, Nujsaubnusi
AU  - Vue N
AD  - Department of Neurology and Neurological Sciences, Stanford University School of 
      Medicine, Stanford, California, USA.
FAU - Balansay, Brianna
AU  - Balansay B
AD  - Department of Neurology and Neurological Sciences, Stanford University School of 
      Medicine, Stanford, California, USA.
FAU - Yu, Furong
AU  - Yu F
AD  - 1] Department of Neurology and Neurological Sciences, Stanford University School 
      of Medicine, Stanford, California, USA. [2] Department of Neurosurgery, Stanford 
      University School of Medicine, Stanford, California, USA.
FAU - Oh, Sekyung
AU  - Oh S
AD  - 1] Department of Neurology and Neurological Sciences, Stanford University School 
      of Medicine, Stanford, California, USA. [2] Department of Neurosurgery, Stanford 
      University School of Medicine, Stanford, California, USA.
FAU - Woo, Pamelyn
AU  - Woo P
AD  - Department of Neurology and Neurological Sciences, Stanford University School of 
      Medicine, Stanford, California, USA.
FAU - Chen, Spenser
AU  - Chen S
AD  - Department of Neurology and Neurological Sciences, Stanford University School of 
      Medicine, Stanford, California, USA.
FAU - Ponnuswami, Anitha
AU  - Ponnuswami A
AD  - Department of Neurology and Neurological Sciences, Stanford University School of 
      Medicine, Stanford, California, USA.
FAU - Monje, Michelle
AU  - Monje M
AD  - Department of Neurology and Neurological Sciences, Stanford University School of 
      Medicine, Stanford, California, USA.
FAU - Atwood, Scott X
AU  - Atwood SX
AD  - Program in Epithelial Biology, Stanford University School of Medicine, Stanford, 
      California, USA.
FAU - Whitson, Ramon J
AU  - Whitson RJ
AD  - Program in Epithelial Biology, Stanford University School of Medicine, Stanford, 
      California, USA.
FAU - Mitra, Siddhartha
AU  - Mitra S
AD  - Department of Neurosurgery, Stanford University School of Medicine, Stanford, 
      California, USA.
FAU - Cheshier, Samuel H
AU  - Cheshier SH
AD  - Department of Neurosurgery, Stanford University School of Medicine, Stanford, 
      California, USA.
FAU - Qi, Jun
AU  - Qi J
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 
      Massachusetts, USA.
FAU - Beroukhim, Rameen
AU  - Beroukhim R
AD  - 1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, 
      Massachusetts, USA. [2] Broad Institute of MIT and Harvard, Cambridge, 
      Massachusetts, USA. [3] Department of Medical Oncology, Dana-Farber Cancer 
      Institute, Boston, Massachusetts, USA.
FAU - Tang, Jean Y
AU  - Tang JY
AD  - Program in Epithelial Biology, Stanford University School of Medicine, Stanford, 
      California, USA.
FAU - Wechsler-Reya, Rob
AU  - Wechsler-Reya R
AD  - Sanford-Burnham Medical Research, La Jolla, California, USA.
FAU - Oro, Anthony E
AU  - Oro AE
AUID- ORCID: 000000026261138X
AD  - Program in Epithelial Biology, Stanford University School of Medicine, Stanford, 
      California, USA.
FAU - Link, Brian A
AU  - Link BA
AD  - Department of Cell Biology, Neurobiology and Anatomy, Medical College of 
      Wisconsin, Milwaukee, Wisconsin, USA.
FAU - Bradner, James E
AU  - Bradner JE
AD  - 1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, 
      Massachusetts, USA. [2] Broad Institute of MIT and Harvard, Cambridge, 
      Massachusetts, USA. [3] Department of Medical Oncology, Dana-Farber Cancer 
      Institute, Boston, Massachusetts, USA.
FAU - Cho, Yoon-Jae
AU  - Cho YJ
AD  - 1] Department of Neurology and Neurological Sciences, Stanford University School 
      of Medicine, Stanford, California, USA. [2] Department of Neurosurgery, Stanford 
      University School of Medicine, Stanford, California, USA. [3] Stanford Cancer 
      Institute, Stanford University Medical Center, Stanford, California, USA.
LA  - eng
GR  - U01 CA176287/CA/NCI NIH HHS/United States
GR  - R01 EY014167/EY/NEI NIH HHS/United States
GR  - U01-CA176287/CA/NCI NIH HHS/United States
GR  - R01 AR054780/AR/NIAMS NIH HHS/United States
GR  - R01 CA159859/CA/NCI NIH HHS/United States
GR  - R01 EY016060/EY/NEI NIH HHS/United States
GR  - R01-CA159859/CA/NCI NIH HHS/United States
GR  - R01 AR046786/AR/NIAMS NIH HHS/United States
GR  - R01 CA157895/CA/NCI NIH HHS/United States
GR  - P30 EY001931/EY/NEI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20140629
PL  - United States
TA  - Nat Med
JT  - Nature medicine
JID - 9502015
RN  - 0 ((+)-JQ1 compound)
RN  - 0 (Azepines)
RN  - 0 (Brd4 protein, mouse)
RN  - 0 (Gli1 protein, mouse)
RN  - 0 (Gli2 protein, mouse)
RN  - 0 (Hedgehog Proteins)
RN  - 0 (Kruppel-Like Transcription Factors)
RN  - 0 (Ligands)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Transcription Factors)
RN  - 0 (Triazoles)
RN  - 0 (Zinc Finger Protein GLI1)
RN  - 0 (Zinc Finger Protein Gli2)
SB  - IM
MH  - Animals
MH  - Azepines/pharmacology
MH  - *Epigenesis, Genetic
MH  - Hedgehog Proteins/*genetics/metabolism
MH  - Kruppel-Like Transcription Factors/genetics
MH  - Ligands
MH  - Mice
MH  - Neoplasms, Experimental/pathology
MH  - Nuclear Proteins/metabolism/*physiology
MH  - Promoter Regions, Genetic
MH  - Signal Transduction/physiology
MH  - Transcription Factors/metabolism/*physiology
MH  - *Transcription, Genetic
MH  - Triazoles/pharmacology
MH  - Zinc Finger Protein GLI1
MH  - Zinc Finger Protein Gli2
PMC - PMC4108909
MID - NIHMS600565
COIS- Conflict of Interest: The Dana-Farber Cancer Institute has licensed drug-like 
      derivatives of JQ1 prepared in the Bradner laboratory to Tensha Therapeutics for 
      clinical translation as cancer therapeutics. Dana-Farber and Dr. Bradner have 
      been provided minority equity shares in Tensha. Dr. Qi has a consultant agreement 
      with Tensha Therapeutics.
EDAT- 2014/06/30 06:00
MHDA- 2014/09/23 06:00
PMCR- 2015/01/01
CRDT- 2014/06/30 06:00
PHST- 2014/03/18 00:00 [received]
PHST- 2014/05/29 00:00 [accepted]
PHST- 2014/06/30 06:00 [entrez]
PHST- 2014/06/30 06:00 [pubmed]
PHST- 2014/09/23 06:00 [medline]
PHST- 2015/01/01 00:00 [pmc-release]
AID - nm.3613 [pii]
AID - 10.1038/nm.3613 [doi]
PST - ppublish
SO  - Nat Med. 2014 Jul;20(7):732-40. doi: 10.1038/nm.3613. Epub 2014 Jun 29.