FOXO3a and Post-translational Modifications Mediate Glucocorticoid Sensitivity in Acute B-ALL
File(s)
Accepted version
Author(s)
Type
Journal Article
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 was 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 post-translational 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 post-translational events can be exploited as biomarkers for B-ALL diagnosis and as drug targets for B-ALL treatment, particularly for overcoming the glucocorticoid resistance.
Date Issued
2015-09-16
Date Acceptance
2015-09-10
Citation
Molecular Cancer Research
ISSN
1557-3125
Publisher
American Association for Cancer Research
Start Page
1578
End Page
1590
Journal / Book Title
Molecular Cancer Research
Volume
13
Copyright Statement
© 2015 American Association for Cancer Research.
Subjects
FOXO3a
B-ALL
B acute lymphoblastic leukaemia
glucocorticoid
drug resistance phosphorylation
acetylation
Publication Status
Accepted