Targeting non-canonical activation of GLI1 by the SOX2-BRD4 transcriptional complex improves the efficacy of HEDGEHOG pathway inhibition in melanoma.
Animals
Antineoplastic Combined Chemotherapy Protocols
/ pharmacology
Cell Cycle Proteins
/ antagonists & inhibitors
Cell Line, Tumor
Cell Proliferation
/ drug effects
Dipeptides
/ administration & dosage
Drug Synergism
Female
Guanidines
/ administration & dosage
Hedgehog Proteins
/ antagonists & inhibitors
Heterocyclic Compounds, 3-Ring
/ administration & dosage
Humans
Melanoma
/ drug therapy
Mice
Mice, Nude
Molecular Targeted Therapy
SOXB1 Transcription Factors
/ metabolism
Signal Transduction
/ drug effects
Smoothened Receptor
/ antagonists & inhibitors
Spheroids, Cellular
Transcription Factors
/ antagonists & inhibitors
Xenograft Model Antitumor Assays
Zinc Finger Protein GLI1
/ metabolism
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
06 2021
06 2021
Historique:
received:
04
12
2020
accepted:
07
04
2021
revised:
22
03
2021
pubmed:
8
5
2021
medline:
13
1
2022
entrez:
7
5
2021
Statut:
ppublish
Résumé
Despite the development of new targeted and immune therapies, the prognosis of metastatic melanoma remains bleak. Therefore, it is critical to better understand the mechanisms controlling advanced melanoma to develop more effective treatment regimens. Hedgehog/GLI (HH/GLI) signaling inhibitors targeting the central pathway transducer Smoothened (SMO) have shown to be clinical efficacious in skin cancer; however, several mechanisms of non-canonical HH/GLI pathway activation limit their efficacy. Here, we identify a novel SOX2-BRD4 transcriptional complex driving the expression of GLI1, the final effector of the HH/GLI pathway, providing a novel mechanism of non-canonical SMO-independent activation of HH/GLI signaling in melanoma. Consistently, we find a positive correlation between the expression of GLI1 and SOX2 in human melanoma samples and cell lines. Further, we show that combined targeting of canonical HH/GLI pathway with the SMO inhibitor MRT-92 and of the SOX2-BRD4 complex using a potent Proteolysis Targeted Chimeras (PROTACs)-derived BRD4 degrader (MZ1), yields a synergistic anti-proliferative effect in melanoma cells independently of their BRAF, NRAS, and NF1 mutational status, with complete abrogation of GLI1 expression. Combination of MRT-92 and MZ1 strongly potentiates the antitumor effect of either drug as single agents in an orthotopic melanoma model. Together, our data provide evidence of a novel mechanism of non-canonical activation of GLI1 by the SOX2-BRD4 transcriptional complex, and describe the efficacy of a new combinatorial treatment for a subset of melanomas with an active SOX2-BRD4-GLI1 axis.
Identifiants
pubmed: 33958721
doi: 10.1038/s41388-021-01783-9
pii: 10.1038/s41388-021-01783-9
pmc: PMC8175236
doi:
Substances chimiques
BRD4 protein, human
0
Cell Cycle Proteins
0
Dipeptides
0
GLI1 protein, human
0
Guanidines
0
Hedgehog Proteins
0
Heterocyclic Compounds, 3-Ring
0
MRT-92
0
MZ1 compound
0
SMO protein, human
0
SOX2 protein, human
0
SOXB1 Transcription Factors
0
Smoothened Receptor
0
Transcription Factors
0
Zinc Finger Protein GLI1
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3799-3814Subventions
Organisme : NCI NIH HHS
ID : P30 CA015083
Pays : United States
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