Noncanonical Regulation of the Hedgehog Mediator GLI1 by c-MYC in Burkitt Lymphoma
| Autor: | Maria Proytcheva, Philip M. Iannaccone, Stephen Iannaccone, Karl Frederic Vieux, Elizabeth Hyjek, David O. Walterhouse, Marisa Gallant, Joon Won Yoon, Marilyn L. G. Lamm |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Cancer Research
Indian hedgehog Cyclopamine Apoptosis Zinc Finger Protein GLI1 Proto-Oncogene Proteins c-myc Mice chemistry.chemical_compound immune system diseases GLI1 Cell Line Tumor hemic and lymphatic diseases medicine Animals Humans Hedgehog Proteins Cilia Molecular Biology Hedgehog Regulation of gene expression integumentary system biology Veratrum Alkaloids medicine.disease biology.organism_classification Burkitt Lymphoma Hedgehog signaling pathway Up-Regulation Lymphoma Gene Expression Regulation Neoplastic Oncology chemistry NIH 3T3 Cells biology.protein Cancer research 5' Untranslated Regions Chromatin immunoprecipitation Signal Transduction Transcription Factors |
| Zdroj: | Molecular Cancer Research. 11:604-615 |
| ISSN: | 1557-3125 1541-7786 |
| DOI: | 10.1158/1541-7786.mcr-12-0441 |
| Popis: | 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. Mol Cancer Res; 11(6); 604–15. ©2013 AACR. |
| Databáze: | OpenAIRE |
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