ArticleOncogene2021
Targeting non-canonical activation of GLI1 by the SOX2-BRD4 transcriptional complex improves the efficacy of HEDGEHOG pathway inhibition in melanoma.
Article in Oncogene, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 39 citations in OpenAlex.
- Mapping of the hSOX10 Proximal Protein Interactome in Human Melanoma.Journal of proteome research · 2026Article
- Dual Inhibition of KRAS G12D and PI3K/BRD4 signaling overcomes therapeutic resistance in pancreatic cancer.Acta biomaterialia · 2026Article
- PROTAC-based protein degradation: a window of opportunity for melanoma therapy.Journal of biomedical science · 2026Review
- Mapping of the hSOX10 protein interactome in human melanoma.bioRxiv : the preprint server for biology · 2025Article
- The MEK5/ERK5 pathway promotes the activation of the Hedgehog/GLI signaling in melanoma cells.Cellular oncology (Dordrecht, Netherlands) · 2025Article
- Review
- Tumor-derived GLI1 promotes remodeling of the immune tumor microenvironment in melanoma.Journal of experimental & clinical cancer research : CR · 2024Article
- Hedgehog Pathway Inhibition by Novel Small Molecules Impairs Melanoma Cell Migration and Invasion under Hypoxia.Pharmaceuticals (Basel, Switzerland) · 2024Article
- SOX2 Expression Does Not Guarantee Cancer Stem Cell-like Characteristics in Lung Adenocarcinoma.Cells · 2024Article
- Hedgehog signaling in tissue homeostasis, cancers, and targeted therapies.Signal transduction and targeted therapy · 2023Review
- Chemically induced degradation of epigenetic targets.Chemical Society reviews · 2023Review
- Combined targeting of HEDGEHOG signaling and BRD4 as a novel therapeutic option against melanoma.Oncotarget · 2023Article
- The Role of Hedgehog Signaling in the Melanoma Tumor Bone Microenvironment.International journal of molecular sciences · 2023Article
- N6-methyladenine-mediated aberrant activation of the lncRNA SOX2OT-GLI1 loop promotes non-small-cell lung cancer stemness.Cell death discovery · 2023Article
- Combined Inhibition of Smoothened and the DNA Damage Checkpoint WEE1 Exerts Antitumor Activity in Cholangiocarcinoma.Molecular cancer therapeutics · 2023Article
- Understanding the Roles of the Hedgehog Signaling Pathway during T-Cell Lymphopoiesis and in T-Cell Acute Lymphoblastic Leukemia (T-ALL).International journal of molecular sciences · 2023Review
- Multiprotein GLI Transcriptional Complexes as Therapeutic Targets in Cancer.Life (Basel, Switzerland) · 2022Review
- [SOX2-OT/SOX2 axis regulates lung cancer H520 cell migrationNan fang yi ke da xue xue bao = Journal of Southern Medical University · 2022Article
- Gli1 promotes epithelial-mesenchymal transition and metastasis of non-small cell lung carcinoma by regulating snail transcriptional activity and stability.Acta pharmaceutica Sinica. B · 2022Article
- Role of the Hedgehog Pathway and CAXII in Controlling Melanoma Cell Migration and Invasion in Hypoxia.Cancers · 2022Article
Corrections and comments
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Authors and funding
15 authors at 6 institutions in 4 countries.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.