ST3GAL1 is a target of the SOX2-GLI1 transcriptional complex and promotes melanoma metastasis through AXL

Pietrobono, Silvia; Anichini, Giulia; Sala, Cesare; Manetti, Fabrizio; Almada, Luciana L.; Pepe, Sara; Carr, Ryan M.; Paradise, Brooke D.; Sarkaria, Jann N.; Davila, Jaime; Tofani, Lorenzo; Battisti, Ilaria; Arrigoni, Giorgio; Li, Ying; Zhang, Cheng; Li, Hu; Meves, Alexander; Fernández-Zapico, Martín E.; Stecca, Barbara

doi:10.1038/s41467-020-19575-2

Cited by 66 publications

(65 citation statements)

References 62 publications

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“…Chromatin immunoprecipitation assay showed cooccupancy of both TFs at a distal enhancer element located at about 10 kb upstream ST3GAL1 transcription start site. Consistently, authors demonstrated that ST3GAL1 mediates SOX2-and GLI1-induced melanoma invasiveness [21]. This study suggests that regulatory regions other than promoters are involved in transcriptional regulation of ST3GAL1.…”

Section: Regulation Of Sialyltransferase Gene Expressionsupporting

confidence: 65%

“…Silencing of ST3GAL1 suppressed melanoma migration and invasion, and reduced the ability of aggressive melanoma cells to enter the bloodstream, colonize distal organs and survive in the metastatic environment, without affecting melanoma cell proliferation nor orthotopic tumor growth in vivo. Mass spectrometry and functional assays revealed that ST3GAL1 explicates the pro-invasive functions through the receptor tyrosine kinase AXL, and that ST3GAL1-mediated sialylation is able to induce AXL dimerization and activation [21].…”

Section: Sustainingmentioning

confidence: 99%

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Aberrant Sialylation in Cancer: Biomarker and Potential Target for Therapeutic Intervention?

Pietrobono¹,

Stecca²

2021

Cancers

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Sialylation is an integral part of cellular function, governing many biological processes including cellular recognition, adhesion, molecular trafficking, signal transduction and endocytosis. Sialylation is controlled by the levels and the activities of sialyltransferases on glycoproteins and lipids. Altered gene expression of these enzymes in cancer yields to cancer-specific alterations of glycoprotein sialylation. Mounting evidence indicate that hypersialylation is closely associated with cancer progression and metastatic spread, and can be of prognostic significance in human cancer. Aberrant sialylation is not only a result of cancer, but also a driver of malignant phenotype, directly impacting key processes such as tumor cell dissociation and invasion, cell-cell and cell-matrix interactions, angiogenesis, resistance to apoptosis, and evasion of immune destruction. In this review we provide insights on the impact of sialylation in tumor progression, and outline the possible application of sialyltransferases as cancer biomarkers. We also summarize the most promising findings on the development of sialyltransferase inhibitors as potential anti-cancer treatments.

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Section: Regulation Of Sialyltransferase Gene Expressionsupporting

confidence: 65%

Section: Sustainingmentioning

confidence: 99%

Aberrant Sialylation in Cancer: Biomarker and Potential Target for Therapeutic Intervention?

Pietrobono¹,

Stecca²

2021

Cancers

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“…Accordingly, activation of the GLI-SOX2 axis is involved in gemcitabine resistance in pancreatic cancer [ 33 ]. Recently, a reciprocal regulation between SOX2 and GLI1 has been described to fuel aberrant glycosylation/sialylation during melanoma progression [ 34 ]. Altogether, these reports and the present study highlight the importance and the biological relevance of the mutual regulation between SOX2 and GLI transcription factors in cancer.…”

Section: Discussionmentioning

confidence: 99%

“…In conclusion, in this study we provide evidence of a novel mechanism of non-canonical SMO-independent activation of GLI1 by the SOX2-BRD4 axis and describe the efficacy of a combinatorial treatment with a novel SMO inhibitor and the PROTAC-derived BRD4 degrader MZ1 in melanoma. The existence of a reciprocal regulation between SOX2 and GLI1 [ 31 ] (this study), which is involved in the transcriptional activation of genes involved in melanoma progression [ 34 ], highlights the therapeutic potential of targeting this axis to treat a subset of advanced melanomas expressing high levels of SOX2 and GLI1.…”

Section: Discussionmentioning

confidence: 99%

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Targeting non-canonical activation of GLI1 by the SOX2-BRD4 transcriptional complex improves the efficacy of HEDGEHOG pathway inhibition in melanoma

et al. 2021

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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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Nintedanib‐α_Vβ₃ Integrin Ligand Dual‐Targeting Conjugates towards Precision Treatment of Melanoma

et al. 2022

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Dedicated to Professor Cesare Gennari on the occasion of his 70th birthday.Melanoma is the deadliest form of skin cancer, and more than 150,000 cases are diagnosed every year in Europe. New strategies in treatment approved over the past decade, such as immunotherapy and targeted therapy, have prolonged life expectation even in stage IV melanoma patients. However, due to the increasing incidence of this cancer, the development of new therapeutic strategies remains urgent. Recent studies revealed the combination of nintedanib, a tyrosine kinase inhibitor approved as an antifibrotic drug, and immuno-and/or targeted therapy drugs to be promising. Here we present three new dual covalent conjugates, in which a nintedanib unit is permanently linked to a cyclopeptidomimetic ligand for the α V β 3 integrin, a transmembrane receptor involved in cell survival, proliferation and migration, which is overexpressed by tumour cells, and therefore recognized as marker for tumour targeting. In vitro assays on human melanoma tumour cells confirmed the high binding affinity of these conjugates for α V β 3 integrin-positive melanoma cells, as well as their integrinmediated cell internalization. Two of these conjugates were efficient in inhibiting the mitogen activated protein kinase (MAPK) signalling pathway, common to both integrin-and growth factor-biological targets. Such targeted conjugates could therefore be of special interest in melanoma treatment alone or in combination with other anticancer drugs.

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ST3GAL1 is a target of the SOX2-GLI1 transcriptional complex and promotes melanoma metastasis through AXL

Cited by 66 publications

References 62 publications

Aberrant Sialylation in Cancer: Biomarker and Potential Target for Therapeutic Intervention?

Aberrant Sialylation in Cancer: Biomarker and Potential Target for Therapeutic Intervention?

Targeting non-canonical activation of GLI1 by the SOX2-BRD4 transcriptional complex improves the efficacy of HEDGEHOG pathway inhibition in melanoma

Nintedanib‐α_Vβ₃ Integrin Ligand Dual‐Targeting Conjugates towards Precision Treatment of Melanoma

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ST3GAL1 is a target of the SOX2-GLI1 transcriptional complex and promotes melanoma metastasis through AXL

Cited by 66 publications

References 62 publications

Aberrant Sialylation in Cancer: Biomarker and Potential Target for Therapeutic Intervention?

Aberrant Sialylation in Cancer: Biomarker and Potential Target for Therapeutic Intervention?

Targeting non-canonical activation of GLI1 by the SOX2-BRD4 transcriptional complex improves the efficacy of HEDGEHOG pathway inhibition in melanoma

Nintedanib‐αVβ3 Integrin Ligand Dual‐Targeting Conjugates towards Precision Treatment of Melanoma

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Nintedanib‐α_Vβ₃ Integrin Ligand Dual‐Targeting Conjugates towards Precision Treatment of Melanoma