title: HEDGEHOG/GLI-E2F1 axis modulates iASPP expression and function and regulates melanoma cell growth.
abstract: HEDGEHOG (HH) signaling is a key regulator of tissue development and its aberrant activation is involved in several cancer types, including melanoma. We and others have shown a reciprocal cross talk between HH signaling and p53, whose function is often impaired in melanoma. Here we present evidence that both GLI1 and GLI2, the final effectors of HH signaling, regulate the transcription factor E2F1 in melanoma cells, by binding to a functional non-canonical GLI consensus sequence. Consistently, we find a significant correlation between E2F1 and PATCHED1 (PTCH1), GLI1 and GLI2 expression in human melanomas. Functionally, we find that E2F1 is a crucial mediator of HH signaling and it is required for melanoma cell proliferation and xenograft growth induced by activation of the HH pathway. Interestingly, we present evidence that the HH/GLI-E2F1 axis positively modulates the inhibitor of apoptosis-stimulating protein of p53 (iASPP) at multiple levels. HH activation induces iASPP expression through E2F1, which directly binds to iASPP promoter. HH pathway also contributes to iASPP function, by the induction of Cyclin B1 and by the E2F1-dependent regulation of CDK1, which are both involved in iASPP activation. Our data show that activation of HH signaling enhances proliferation in presence of E2F1 and promotes apoptosis in its absence or upon CDK1 inhibition, suggesting that E2F1/iASPP dictates the outcome of HH signaling in melanoma. Together, these findings identify a novel HH/GLI-E2F1-iASPP axis that regulates melanoma cell growth and survival, providing an additional mechanism through which HH signaling restrains p53 proapoptotic function.
authors.affiliation: Laboratory of Tumor Cell Biology, Core Research Laboratory-Istituto Toscano Tumori (CRL-ITT), Florence, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Pandolfi
authors.affiliation: Laboratory of Tumor Cell Biology, Core Research Laboratory-Istituto Toscano Tumori (CRL-ITT), Florence, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Montagnani
authors.affiliation: Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Lapucci
authors.affiliation: Laboratory of Tumor Cell Biology, Core Research Laboratory-Istituto Toscano Tumori (CRL-ITT), Florence, Italy.|Department of Oncology, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Stecca
mesh_terms: D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D016203:CDC2 Protein Kinase / Q000378:metabolism; D049109:Cell Proliferation; D056744:Cyclin B1 / Q000378:metabolism; D050687:E2F1 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008545:Melanoma / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D016297:Mutagenesis, Site-Directed; D041681:NIH 3T3 Cells; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2
chemical_list: D056744:Cyclin B1; D050687:E2F1 Transcription Factor; C000618551:Gli2 protein, mouse; D053823:Hedgehog Proteins; D047908:Intracellular Signaling Peptides and Proteins; D051741:Kruppel-Like Transcription Factors; D015513:Oncogene Proteins; C119612:PPP1R13L protein, human; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; D012097:Repressor Proteins; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2; D016203:CDC2 Protein Kinase