Cargando…

Oncogenic RAS-induced CK1α drives nuclear FOXO proteolysis

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 ho...

Descripción completa

Detalles Bibliográficos
Autores principales: Zhang, F, Virshup, D M, Cheong, J K
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5799771/
https://www.ncbi.nlm.nih.gov/pubmed/28945225
http://dx.doi.org/10.1038/onc.2017.334
_version_ 1783298071706206208
author Zhang, F
Virshup, D M
Cheong, J K
author_facet Zhang, F
Virshup, D M
Cheong, J K
author_sort Zhang, F
collection PubMed
description 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 (CK1α) in an oncogenic RAS-specific manner, but whether this mode of regulation extends to related FOXO family members is unknown. Here we report that CK1α similarly destabilizes FOXO4 in RAS-mutant cells by phosphorylation at serines 265/268. The CK1α-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 CK1α 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.
format Online
Article
Text
id pubmed-5799771
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher Nature Publishing Group
record_format MEDLINE/PubMed
spelling pubmed-57997712018-02-08 Oncogenic RAS-induced CK1α drives nuclear FOXO proteolysis Zhang, F Virshup, D M Cheong, J K Oncogene Original Article 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 (CK1α) in an oncogenic RAS-specific manner, but whether this mode of regulation extends to related FOXO family members is unknown. Here we report that CK1α similarly destabilizes FOXO4 in RAS-mutant cells by phosphorylation at serines 265/268. The CK1α-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 CK1α 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. Nature Publishing Group 2018-01-18 2017-09-25 /pmc/articles/PMC5799771/ /pubmed/28945225 http://dx.doi.org/10.1038/onc.2017.334 Text en Copyright © 2017 The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Original Article
Zhang, F
Virshup, D M
Cheong, J K
Oncogenic RAS-induced CK1α drives nuclear FOXO proteolysis
title Oncogenic RAS-induced CK1α drives nuclear FOXO proteolysis
title_full Oncogenic RAS-induced CK1α drives nuclear FOXO proteolysis
title_fullStr Oncogenic RAS-induced CK1α drives nuclear FOXO proteolysis
title_full_unstemmed Oncogenic RAS-induced CK1α drives nuclear FOXO proteolysis
title_short Oncogenic RAS-induced CK1α drives nuclear FOXO proteolysis
title_sort oncogenic ras-induced ck1α drives nuclear foxo proteolysis
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5799771/
https://www.ncbi.nlm.nih.gov/pubmed/28945225
http://dx.doi.org/10.1038/onc.2017.334
work_keys_str_mv AT zhangf oncogenicrasinducedck1adrivesnuclearfoxoproteolysis
AT virshupdm oncogenicrasinducedck1adrivesnuclearfoxoproteolysis
AT cheongjk oncogenicrasinducedck1adrivesnuclearfoxoproteolysis