TY - JOUR
T1 - Targeting non-canonical activation of GLI1 by the SOX2-BRD4 transcriptional complex improves the efficacy of HEDGEHOG pathway inhibition in melanoma
AU - Pietrobono, Silvia
AU - Gaudio, Eugenio
AU - Gagliardi, Sinforosa
AU - Zitani, Mariapaola
AU - Carrassa, Laura
AU - Migliorini, Francesca
AU - Petricci, Elena
AU - Manetti, Fabrizio
AU - Makukhin, Nikolai
AU - Bond, Adam G.
AU - Paradise, Brooke D.
AU - Ciulli, Alessio
AU - Fernandez-Zapico, Martin E.
AU - Bertoni, Francesco
AU - Stecca, Barbara
N1 - We thank Fritz Aberger (University of Salzburg, Austria) for SOX2 promoter/enhancer reporter plasmids. The BS lab was partially supported by Associazione Italiana per la Ricerca sul Cancro (AIRC) (IG-14184 and IG-23091) and by institutional funding from the Institute for Cancer Research, Prevention and Clinical Network (ISPRO). SP was supported by AIRC fellowship (n. 21168). The AC lab was funded by awards from the UK Biotechnology and Biological Sciences Research Council (BBSRC, grant BB/J001201/2) and the European Research Council (ERC, Starting Grant ERC-2012-StG-311460 DrugE3CRLs). AGB was supported by a Medical Research Scotland PhD studentship (1170-2017).
PY - 2021/6/3
Y1 - 2021/6/3
N2 - 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.
AB - 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.
KW - Cell signalling
KW - Melanoma
UR - http://www.scopus.com/inward/record.url?scp=85105295572&partnerID=8YFLogxK
U2 - 10.1038/s41388-021-01783-9
DO - 10.1038/s41388-021-01783-9
M3 - Article
C2 - 33958721
SN - 0950-9232
VL - 40
SP - 3799
EP - 3814
JO - Oncogene
JF - Oncogene
ER -