Please use this identifier to cite or link to this item: https://doi.org/10.1038/onc.2017.334
Title: Oncogenic RAS-induced CK1? drives nuclear FOXO proteolysis
Authors: Zhang, F 
Virshup, D.M 
Cheong, J.K 
Keywords: casein kinase Ialpha
caspase
nuclear protein
phosphatidylinositol 3 kinase
proteasome
protein FOXO4
protein kinase B
Ras protein
serine
transcription factor FKHRL1
transcription factor FOXO
tumor suppressor protein
unclassified drug
4-(4-(2,3-dihydrobenzo(1,4)dioxin-6-yl)-5-pyridin-2-yl-1H-imidazol-2-yl)benzamide
benzamide derivative
casein kinase Ialpha
FOXO3 protein, human
FOXO4 protein, human
imidazole derivative
KRAS protein, human
proteasome
proteasome inhibitor
protein p21
serine
small interfering RNA
transcription factor
transcription factor FKHRL1
apoptosis
Article
cancer cell line
cancer growth
cell mutant
colon cancer
human
human cell
nuclear export
priority journal
protein degradation
protein expression
protein induction
protein phosphorylation
protein processing
regulatory mechanism
signal transduction
antagonists and inhibitors
cell cycle
cell nucleus
drug effect
genetics
metabolism
mutation
neoplasm
pathology
phosphorylation
protein degradation
tumor cell line
Apoptosis
Benzamides
Casein Kinase Ialpha
Cell Cycle
Cell Line, Tumor
Cell Nucleus
Forkhead Box Protein O3
Humans
Imidazoles
Mutation
Neoplasms
Phosphorylation
Proteasome Endopeptidase Complex
Proteasome Inhibitors
Protein Processing, Post-Translational
Proteolysis
Proto-Oncogene Proteins p21(ras)
RNA, Small Interfering
Serine
Signal Transduction
Transcription Factors
Issue Date: 2018
Publisher: Nature Publishing Group
Citation: Zhang, F, Virshup, D.M, Cheong, J.K (2018). Oncogenic RAS-induced CK1? drives nuclear FOXO proteolysis. Oncogene 37 (3) : 363-376. ScholarBank@NUS Repository. https://doi.org/10.1038/onc.2017.334
Abstract: Evasion of forkhead box O (FOXO) family of longevity-related transcription factors-mediated growth suppression is necessary to promote cancer development. Since somatic alterations or mutations and transcriptional dysregulation of the FOXO genes are infrequent in human cancers, it remains unclear how these tumour suppressors are eliminated from cancer cells. The protein stability of FOXO3A is regulated by Casein Kinase 1 alpha (CK1?) in an oncogenic RAS-specific manner, but whether this mode of regulation extends to related FOXO family members is unknown. Here we report that CK1? similarly destabilizes FOXO4 in RAS-mutant cells by phosphorylation at serines 265/268. The CK1?-dependent phosphoregulation of FOXO4 is primed, in part, by the PI3K/AKT effector axis of oncogenic RAS signalling. In addition, mutant RAS coordinately elevates proteasome subunit expression and proteolytic activity to eradicate nuclear FOXO4 proteins from RAS-mutant cancer cells. Importantly, dual inhibition of CK1? and the proteasome synergistically inhibited the growth of multiple RAS-mutant human cancer cell lines of diverse tissue origin by blockade of nuclear FOXO4 degradation and induction of caspase-dependent apoptosis. Our findings challenge the current paradigm that nuclear export regulates the proteolysis of FOXO3A/4 tumour suppressors in the context of cancer and illustrates how oncogenic RAS-mediated degradation of FOXOs, via post-translational mechanisms, blocks these important tumour suppressors. © 2018 The Author(s).
Source Title: Oncogene
URI: https://scholarbank.nus.edu.sg/handle/10635/175130
ISSN: 0950-9232
DOI: 10.1038/onc.2017.334
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