title: FOXO3a and Posttranslational Modifications Mediate Glucocorticoid Sensitivity in B-ALL.
abstract: Glucocorticoids are widely used to treat B acute lymphoblastic leukemia (B-ALL); however, the molecular mechanism underlying glucocorticoid response and resistance is unclear. In this study, the role and regulation of FOXO3a in mediating the dexamethasone response in B-ALL were investigated. The results show that FOXO3a mediates the cytotoxic function of dexamethasone. In response to dexamethasone, it was found that FOXO3a translocates into the nucleus, where it induces the expression of downstream targets, including p27Kip1 and Bim, important for proliferative arrest and cell death in the sensitive RS4;11 and SUP-B15 B-ALL cells. FOXO3a activation by dexamethasone is mediated partially through the suppression of the PI3K/Akt signaling cascade. Furthermore, two posttranslational modifications were uncovered, phosphorylation on Ser-7 and acetylation on Lys-242/5, that associated with FOXO3a activation by dexamethasone. Immunoblot analysis showed that the phosphorylation on Ser-7 of FOXO3a is associated with p38/JNK activation, whereas the acetylation on Lys-242/5 is correlated with the downregulation of SIRT1/2/6 and the induction of the acetyltransferase CBP/p300. Collectively, these results indicate that FOXO3a is essential for dexamethasone response in B-ALL cells, and its nuclear translocation and activation is associated with its phosphorylation on Ser-7 and acetylation on Lys-242/245. These posttranslational events can be exploited as biomarkers for B-ALL diagnosis and as drug targets for B-ALL treatment, particularly for overcoming the glucocorticoid resistance.
  
  
  CONCLUSIONS
  FOXO3a and its posttranslational regulation are essential for dexamethasone response, and targeting FOXO3a and sirtuins may enhance the dexamethasone-induced cytotoxicity in B-ALL cells.
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), London, United Kingdom. Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia, University of Padova, Padova, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Consolaro
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), London, United Kingdom.
authors.forename: Sadaf
authors.initials: S
authors.lastname: Ghaem-Maghami
authors.affiliation: Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia, University of Padova, Padova, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Bortolozzi
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), London, United Kingdom.
authors.forename: Stefania
authors.initials: S
authors.lastname: Zona
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), London, United Kingdom.
authors.forename: Mattaka
authors.initials: M
authors.lastname: Khongkow
authors.affiliation: Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia, University of Padova, Padova, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Basso
authors.affiliation: Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia, University of Padova, Padova, Italy. eric.lam@imperial.ac.uk giampietro.viola.1@unipd.it.
authors.forename: Giampietro
authors.initials: G
authors.lastname: Viola
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), London, United Kingdom. eric.lam@imperial.ac.uk giampietro.viola.1@unipd.it.
authors.forename: Eric W-F
authors.initials: EW
authors.lastname: Lam
mesh_terms: D000107:Acetylation; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D010766:Phosphorylation; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D015398:Signal Transduction; D016896:Treatment Outcome
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D005938:Glucocorticoids; D003907:Dexamethasone