title: FBXW7 regulates glucocorticoid response in T-cell acute lymphoblastic leukaemia by targeting the glucocorticoid receptor for degradation.
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.
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia. amalyukova@ccia.unsw.edu.au
authors.forename: A
authors.initials: A
authors.lastname: Malyukova
authors.forename: S
authors.initials: S
authors.lastname: Brown
authors.forename: R
authors.initials: R
authors.lastname: Papa
authors.forename: R
authors.initials: R
authors.lastname: O'Brien
authors.forename: J
authors.initials: J
authors.lastname: Giles
authors.forename: T N
authors.initials: TN
authors.lastname: Trahair
authors.forename: L
authors.initials: L
authors.lastname: Dalla Pozza
authors.forename: R
authors.initials: R
authors.lastname: Sutton
authors.forename: T
authors.initials: T
authors.lastname: Liu
authors.forename: M
authors.initials: M
authors.lastname: Haber
authors.forename: M D
authors.initials: MD
authors.lastname: Norris
authors.forename: R B
authors.initials: RB
authors.lastname: Lock
authors.forename: O
authors.initials: O
authors.lastname: Sangfelt
authors.forename: G M
authors.initials: GM
authors.lastname: Marshall
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D044783:F-Box Proteins / Q000235:genetics / Q000502:physiology*; D000073979:F-Box-WD Repeat-Containing Protein 7; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D010766:Phosphorylation; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D055550:Protein Stability; D011965:Receptors, Glucocorticoid / Q000737:chemistry / Q000187:drug effects* / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000502:physiology*
chemical_list: D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; C411470:glucocorticoid receptor alpha; D044767:Ubiquitin-Protein Ligases