Abstract
Loss of function mutation in FBXW7, an E3 ubiquitin ligase, is associated with good prognosis and early glucocorticoid treatment response in childhood T-cell acute lymphoblastic leukemia (T-ALL) by unknown mechanisms. Here, we show that FBXW7 targets the glucocorticoid receptor α (GRα) for ubiquitylation and proteasomal degradation in a manner dependent on glycogen synthase kinase 3 β-mediated phsophorylation. FBXW7 inactivation caused elevated GRα levels, and enhanced the transcriptional response to glucocorticoids. There was significant enhancement of GR transcriptional responses in FBXW7-deficient cell lines and primary T-ALL samples, in particular, for those pro-apoptotic regulatory proteins, BIM and PUMA. Reduced FBXW7 expression or function promoted glucocorticoid sensitivity, but not sensitivity to other chemotherapeutic agents used in T-ALL. Moreover, this was a general feature of different cancer cell types. Taken together, our work defines GRα as a novel FBXW7 substrate and demonstrates that favorable patient prognosis in T-ALL is associated with FBXW7 mutations due to enhanced GRα levels and steroid sensitivity. These findings suggest that inactivation of FBXW7, a putative tumor suppressor protein, may create a synthetic lethal state in the presence of specific anticancer therapies.
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Acknowledgements
We thank Bert Vogelstein (Johns Hopkins University, Baltimore, MD) for kindly providing FBXW7-deficient HCT 116 cells and parental control cells. Children’s Cancer Institute Australia for Medical Research is affiliated with the Sydney Children’s Hospital and the University of New South Wales. This study was supported by grants from National Health and Medical Research Council of Australia (G.M., M.N., M.H.), Cancer Council New South Wales (G.M., M.N., M.H.), Steven Walter Children’s Cancer Foundation (G.M.), Cancer Institute New South Wales (G.M., M.N., M.H.), and Leukemia Foundation (G.M.), Swedish Society for Medical Research (A.M.), the Swedish Cancer Foundation, the Swedish Research Council (O.S.), the Swedish Children’s Cancer Foundation and Karolinska Institute Foundations (O.S.).
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Malyukova, A., Brown, S., Papa, R. et al. FBXW7 regulates glucocorticoid response in T-cell acute lymphoblastic leukaemia by targeting the glucocorticoid receptor for degradation. Leukemia 27, 1053–1062 (2013). https://doi.org/10.1038/leu.2012.361
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DOI: https://doi.org/10.1038/leu.2012.361
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