title: Noncanonical regulation of the Hedgehog mediator GLI1 by c-MYC in Burkitt lymphoma.
abstract: Although Hedgehog signaling plays a major role in GLI1 transcription, there is now evidence suggesting that other pathways/genes, such as c-MYC, may also regulate GLI1 expression. We initiated studies in Burkitt lymphoma cells, which constitutively express c-MYC due to a chromosomal translocation, to determine whether Hedgehog or c-MYC regulates GLI1 expression. We show that all Burkitt lymphoma cell lines tested express GLI1, PTCH1, and SMO and that five of six Burkitt lymphomas express GLI1. Exposure to Sonic or Indian Hedgehog or cyclopamine (SMO inhibitor) does not modulate GLI1 expression, cell proliferation, or apoptosis in most Burkitt lymphoma cell lines. Sequence analysis of PTCH1, SMO, and SuFu failed to show mutations that might explain the lack of Hedgehog responsiveness, and we did not detect primary cilia, which may contribute to it. We show that c-MYC interacts with the 5'-regulatory region of GLI1, using chromatin immunoprecipitation (ChIP) assay, and E-box-dependent transcriptional activation of GLI1 by c-MYC in NIH3T3 and HeLa cells. The c-MYC small-molecule inhibitor 10058-F4 downregulates GLI1 mRNA and protein and reduces the viability of Burkitt lymphoma cells. Inhibition of GLI1 by GANT61 increases apoptosis and reduces viability of some Burkitt lymphoma cells. Collectively, our data provide evidence that c-MYC directly regulates GLI1 and support an antiapoptotic role for GLI1 in Burkitt lymphoma. Burkitt lymphoma cells do not seem to be Hedgehog responsive. These findings suggest a mechanism for resistance to SMO inhibitors and have implications for using SMO inhibitors to treat human cancers.
authors.affiliation: Developmental Biology Program, Ann & Robert H Lurie Children's Hospital of Chicago Research Center, Northwestern University Feinberg School of Medicine, Illinois 60614, USA.
authors.forename: Joon Won
authors.initials: JW
authors.lastname: Yoon
authors.forename: Marisa
authors.initials: M
authors.lastname: Gallant
authors.forename: Marilyn L G
authors.initials: ML
authors.lastname: Lamm
authors.forename: Stephen
authors.initials: S
authors.lastname: Iannaccone
authors.forename: Karl-Frederic
authors.initials: KF
authors.lastname: Vieux
authors.forename: Maria
authors.initials: M
authors.lastname: Proytcheva
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hyjek
authors.forename: Philip
authors.initials: P
authors.lastname: Iannaccone
authors.forename: David
authors.initials: D
authors.lastname: Walterhouse
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002051:Burkitt Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002923:Cilia / Q000187:drug effects / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D014704:Veratrum Alkaloids / Q000494:pharmacology; D000071676:Zinc Finger Protein GLI1
chemical_list: D020121:5' Untranslated Regions; C400551:GLI1 protein, human; D053823:Hedgehog Proteins; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; D014704:Veratrum Alkaloids; D000071676:Zinc Finger Protein GLI1; C000541:cyclopamine