title: Nuclear GSK3β promotes tumorigenesis by phosphorylating KDM1A and inducing its deubiquitylation by USP22.
abstract: Emerging evidence has shown that GSK3β plays oncogenic roles in multiple tumour types; however, the underlying mechanisms remain largely unknown. Here, 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 Ser683 upon priming phosphorylation of KDM1A Ser687 by CK1α. Phosphorylation of KDM1A induces its binding with and deubiquitylation by USP22, leading to KDM1A stabilization. GSK3β- and USP22-dependent KDM1A stabilization is required for the demethylation of histone H3K4, thereby repressing BMP2, CDKN1A and GATA6 transcription, which results in 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 tumour xenografts to chemotherapy in mice via KDM1A downregulation and improves survival. Our findings demonstrate that nuclear GSK3β- and USP22-mediated KDM1A stabilization is essential for glioblastoma tumorigenesis.
authors: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors: Aidong
authors: A
authors: Zhou
authors: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors: Kangyu
authors: K
authors: Lin
authors: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.|Cancer Biology Program, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas, USA.
authors: Sicong
authors: S
authors: Zhang
authors: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors: Yaohui
authors: Y
authors: Chen
authors: Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China.
authors: Nu
authors: N
authors: Zhang
authors: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors: Jianfei
authors: J
authors: Xue
authors: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors: Zhongyong
authors: Z
authors: Wang
authors: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors: Kenneth D
authors: KD
authors: Aldape
authors: Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.|Cancer Biology Program, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas, USA.
authors: Keping
authors: K
authors: Xie
authors: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors: James R
authors: JR
authors: Woodgett
authors: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.|Cancer Biology Program, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas, USA.
authors: Suyun
authors: S
authors: Huang
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000187:drug effects / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D010450:Endopeptidases / Q000378:metabolism*; D005909:Glioblastoma / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism*; D056466:Histone Demethylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008819:Mice, Nude; D010766:Phosphorylation / Q000187:drug effects; D013830:Thiadiazoles / Q000494:pharmacology; D013869:Thiolester Hydrolases / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase; D054875:Ubiquitination
chemical_list: D006657:Histones; D013830:Thiadiazoles; D056466:Histone Demethylases; C504076:KDM1a protein, mouse; C495195:KDM1A protein, human; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D013869:Thiolester Hydrolases; D010450:Endopeptidases; C584444:USP22 protein, mouse; D043222:Ubiquitin Thiolesterase; C527170:Usp22 protein, human; C520571:tideglusib