Noncanonical regulation of the Hedgehog mediator GLI1 by c-MYC in Burkitt lymphoma.
| Autor: | Yoon JW; Developmental Biology Program, Ann & Robert H Lurie Children's Hospital of Chicago Research Center, Northwestern University Feinberg School of Medicine, Illinois 60614, USA., Gallant M, Lamm ML, Iannaccone S, Vieux KF, Proytcheva M, Hyjek E, Iannaccone P, Walterhouse D |
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| Jazyk: | angličtina |
| Zdroj: | Molecular cancer research : MCR [Mol Cancer Res] 2013 Jun; Vol. 11 (6), pp. 604-15. Date of Electronic Publication: 2013 Mar 22. |
| DOI: | 10.1158/1541-7786.MCR-12-0441 |
| Abstrakt: | 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. (©2013 AACR) |
| Databáze: | MEDLINE |
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