title: Tumor-Derived Suppressor of Fused Mutations Reveal Hedgehog Pathway Interactions.
abstract: The Hedgehog pathway is a potent regulator of cellular growth and plays a central role in the development of many cancers including basal cell carcinoma (BCC). The majority of BCCs arise from mutations in the Patched receptor resulting in constitutive activation of the Hedgehog pathway. Secondary driver mutations promote BCC oncogenesis and occur frequently due to the high mutational burden resulting from sun exposure of the skin. Here, we uncover novel secondary mutations in Suppressor of Fused (SUFU), the major negative regulator of the Hedgehog pathway. SUFU normally binds to a Hedgehog transcriptional activator, GLI1, in order to prevent it from initiating transcription of Hedgehog target genes. We sequenced tumor-normal pairs from patients with early sporadic BCCs. This resulted in the discovery of nine mutations in SUFU, which were functionally investigated to determine whether they help drive BCC formation. Our results show that four of the SUFU mutations inappropriately activate the Hedgehog pathway, suggesting they may act as driver mutations for BCC development. Indeed, all four of the loss of function SUFU variants were found to disrupt its binding to GLI, leading to constitutive pathway activation. Our results from functional characterization of these mutations shed light on SUFU's role in Hedgehog signaling, tumor progression, and highlight a way in which BCCs can arise.
authors.affiliation: Program in Epithelial Biology and Department of Dermatology, Stanford University School of Medicine, Stanford, CA, United States of America.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Urman
authors.affiliation: Program in Epithelial Biology and Department of Dermatology, Stanford University School of Medicine, Stanford, CA, United States of America.
authors.forename: Amar
authors.initials: A
authors.lastname: Mirza
authors.affiliation: Program in Epithelial Biology and Department of Dermatology, Stanford University School of Medicine, Stanford, CA, United States of America.|Department of Developmental and Cell Biology, Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, CA, United States of America.
authors.forename: Scott X
authors.initials: SX
authors.lastname: Atwood
authors.affiliation: Program in Epithelial Biology and Department of Dermatology, Stanford University School of Medicine, Stanford, CA, United States of America.
authors.forename: Ramon J
authors.initials: RJ
authors.lastname: Whitson
authors.affiliation: Program in Epithelial Biology and Department of Dermatology, Stanford University School of Medicine, Stanford, CA, United States of America.
authors.forename: Kavita Y
authors.initials: KY
authors.lastname: Sarin
authors.affiliation: Program in Epithelial Biology and Department of Dermatology, Stanford University School of Medicine, Stanford, CA, United States of America.
authors.forename: Jean Y
authors.initials: JY
authors.lastname: Tang
authors.affiliation: Program in Epithelial Biology and Department of Dermatology, Stanford University School of Medicine, Stanford, CA, United States of America.
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Oro
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D002280:Basal Cell Carcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D018450:Disease Progression; D057809:HEK293 Cells; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D009154:Mutation; D041681:NIH 3T3 Cells; D011487:Protein Conformation; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D055815:Young Adult; D000071676:Zinc Finger Protein GLI1 / Q000378:metabolism
chemical_list: D053823:Hedgehog Proteins; D012097:Repressor Proteins; C490764:SUFU protein, human; D000071676:Zinc Finger Protein GLI1