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Nuclear GSK3β promotes tumorigenesis by phosphorylating KDM1A and inducing its deubiquitination by USP22
Emerging evidences have shown that GSK3β plays oncogenic roles in multiple tumor types; however, the underlying mechanisms remain largely unknown. Herein, we show that nuclear GSK3β is responsible for the accumulation of the histone demethylase KDM1A and critically regulates histone H3K4 methylation...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5026327/ https://www.ncbi.nlm.nih.gov/pubmed/27501329 http://dx.doi.org/10.1038/ncb3396 |
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author | Zhou, Aidong Lin, Kangyu Zhang, Sicong Chen, Yaohui Zhang, Nu Xue, Jianfei Wang, Zhongyong Aldape, Kenneth D. Xie, Keping Woodgett, James R. Huang, Suyun |
author_facet | Zhou, Aidong Lin, Kangyu Zhang, Sicong Chen, Yaohui Zhang, Nu Xue, Jianfei Wang, Zhongyong Aldape, Kenneth D. Xie, Keping Woodgett, James R. Huang, Suyun |
author_sort | Zhou, Aidong |
collection | PubMed |
description | Emerging evidences have shown that GSK3β plays oncogenic roles in multiple tumor types; however, the underlying mechanisms remain largely unknown. Herein, we show that nuclear GSK3β is responsible for the accumulation of the histone demethylase KDM1A and critically regulates histone H3K4 methylation during tumorigenesis. GSK3β phosphorylates KDM1A serine 683 upon priming phosphorylation of KDM1A serine 687 by CK1α. Phosphorylation of KDM1A induces its binding with and deubiquitination by USP22, leading to KDM1A stabilization. GSK3β and USP22-dependent KDM1A stabilization is required for the demethylation of histone H3K4, thereby repression of BMP2, CDKN1A, and GATA6 transcription, cancer stem cell self-renewal, and glioblastoma tumorigenesis. In human glioblastoma specimens, KDM1A levels are correlated with nuclear GSK3β and USP22 levels. Furthermore, a GSK3 inhibitor tideglusib sensitizes tumor xenograft to chemotherapy in mice via KDM1A down-regulation and improves survival. Our findings demonstrate that nuclear GSK3β and USP22-mediated KDM1A stabilization is essential for glioblastoma tumorigenesis. |
format | Online Article Text |
id | pubmed-5026327 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
record_format | MEDLINE/PubMed |
spelling | pubmed-50263272017-02-08 Nuclear GSK3β promotes tumorigenesis by phosphorylating KDM1A and inducing its deubiquitination by USP22 Zhou, Aidong Lin, Kangyu Zhang, Sicong Chen, Yaohui Zhang, Nu Xue, Jianfei Wang, Zhongyong Aldape, Kenneth D. Xie, Keping Woodgett, James R. Huang, Suyun Nat Cell Biol Article Emerging evidences have shown that GSK3β plays oncogenic roles in multiple tumor types; however, the underlying mechanisms remain largely unknown. Herein, we show that nuclear GSK3β is responsible for the accumulation of the histone demethylase KDM1A and critically regulates histone H3K4 methylation during tumorigenesis. GSK3β phosphorylates KDM1A serine 683 upon priming phosphorylation of KDM1A serine 687 by CK1α. Phosphorylation of KDM1A induces its binding with and deubiquitination by USP22, leading to KDM1A stabilization. GSK3β and USP22-dependent KDM1A stabilization is required for the demethylation of histone H3K4, thereby repression of BMP2, CDKN1A, and GATA6 transcription, cancer stem cell self-renewal, and glioblastoma tumorigenesis. In human glioblastoma specimens, KDM1A levels are correlated with nuclear GSK3β and USP22 levels. Furthermore, a GSK3 inhibitor tideglusib sensitizes tumor xenograft to chemotherapy in mice via KDM1A down-regulation and improves survival. Our findings demonstrate that nuclear GSK3β and USP22-mediated KDM1A stabilization is essential for glioblastoma tumorigenesis. 2016-08-08 2016-09 /pmc/articles/PMC5026327/ /pubmed/27501329 http://dx.doi.org/10.1038/ncb3396 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Zhou, Aidong Lin, Kangyu Zhang, Sicong Chen, Yaohui Zhang, Nu Xue, Jianfei Wang, Zhongyong Aldape, Kenneth D. Xie, Keping Woodgett, James R. Huang, Suyun Nuclear GSK3β promotes tumorigenesis by phosphorylating KDM1A and inducing its deubiquitination by USP22 |
title | Nuclear GSK3β promotes tumorigenesis by phosphorylating KDM1A and inducing its deubiquitination by USP22 |
title_full | Nuclear GSK3β promotes tumorigenesis by phosphorylating KDM1A and inducing its deubiquitination by USP22 |
title_fullStr | Nuclear GSK3β promotes tumorigenesis by phosphorylating KDM1A and inducing its deubiquitination by USP22 |
title_full_unstemmed | Nuclear GSK3β promotes tumorigenesis by phosphorylating KDM1A and inducing its deubiquitination by USP22 |
title_short | Nuclear GSK3β promotes tumorigenesis by phosphorylating KDM1A and inducing its deubiquitination by USP22 |
title_sort | nuclear gsk3β promotes tumorigenesis by phosphorylating kdm1a and inducing its deubiquitination by usp22 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5026327/ https://www.ncbi.nlm.nih.gov/pubmed/27501329 http://dx.doi.org/10.1038/ncb3396 |
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