Nuclear GSK3β promotes tumorigenesis by phosphorylating KDM1A and inducing its deubiquitylation by USP22

Zhou, Aidong; Lin, Kangyu; Zhang, Sicong; Chen, Yaohui; Zhang, Nu; Xue, Jianfei; Wang, Zhongyong; Aldape, Kenneth; Xie, Keping; Woodgett, James R.; Huang, Suyun

doi:10.1038/ncb3396

Cited by 132 publications

(136 citation statements)

References 53 publications

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“…In vitro limiting dilution assay (LDA) was performed as described previously (Zhou et al, 2016). Briefly, dissociated GSC cells were seeded in 96-well plates at density of 5, 10, 20, 50, 100 or 200 cells per well and each well was examined for formation of tumorspheres after 7 days.…”

Section: Star Methodsmentioning

confidence: 99%

m 6 A Demethylase ALKBH5 Maintains Tumorigenicity of Glioblastoma Stem-like Cells by Sustaining FOXM1 Expression and Cell Proliferation Program

et al. 2017

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SUMMARY The dynamic and reversible N6-methyladenosine (m6A) RNA modification installed and erased by N6-methyltransferases and demethylases regulates gene expression and cell fate. We show that the m6A demethylase ALKBH5 is highly expressed in glioblastoma stem-like cells (GSCs). Silencing ALKBH5 suppresses the proliferation of patient-derived GSCs. Integrated transcriptome and m6A-seq analyses revealed altered expression of certain ALKBH5 target genes, including the transcription factor FOXM1. ALKBH5 demethylates FOXM1 nascent transcripts, leading to enhanced FOXM1 expression. Further, a long noncoding RNA antisense to FOXM1 (FOXM1-AS) promotes the interaction of ALKBH5 with FOXM1 nascent transcripts. Depleting ALKBH5 and FOXM1-AS disrupted GSC tumorigenesis through the FOXM1 axis. Our work uncovers a critical function for ALKBH5 and provides insight into critical roles of m6A methylation in glioblastoma.

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Section: Star Methodsmentioning

confidence: 99%

m 6 A Demethylase ALKBH5 Maintains Tumorigenicity of Glioblastoma Stem-like Cells by Sustaining FOXM1 Expression and Cell Proliferation Program

et al. 2017

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“…Because USP22 is functionally correlated with Wnt/β-catenin signaling regulators and proteins Foxm1 and GSKβ [7, 16], we hypothesized that USP22 maintains CRC cell stemness and tumorigenesis through Wnt/β-catenin signaling. To explore this hypothesis, we performed RT-PCR and western blot assays for Wnt/β-catenin signaling target genes (Axin2, MYC and Cyclin D1) in USP22 knockdown Caco2 and HCT15 stem cells.…”

Section: Resultsmentioning

confidence: 99%

Ubiquitin-Specific Peptidase 22 Contributes to Colorectal Cancer Stemness and Chemoresistance via Wnt/β-Catenin Pathway

Jiang

Song

et al. 2018

Cell Physiol Biochem

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Background/Aims: Two major barriers to the successful treatment of colorectal cancer (CRC) are the development of stem cell-like characteristics (stemness) and chemoresistance. Ubiquitin-specific peptidase 22 (USP22) is a deubiquitinating enzyme and putative CRC marker that has emerged as a potential cause of both phenomena in CRC. There is evidence that USP22 acts through the Wnt/β-catenin pathway and that downregulation of the latter may reduce chemoresistance. Methods: In this study, we used CRC tissue specimens from human patients as well as human CRC cell lines to evaluate the role of USP22 in CRC stemness and chemoresistance in vitro and in vivo. RT-PCR and western blot were used for gene expression analyses. Immunohistochemistry was performed for USP22 expression in clinical samples. CD133 levels were analyzed by flow cytometry. Sphere formation and MTT assays were used for self-renewal and proliferation analysis. Chemoresistance was evaluated by cell viability and sphere formation assays. Results: We found a significant increase of USP22 in recurrent CRC and chemoresistant CRC cells as compared to primary CRC and non-chemoresistant CRC cells, respectively. We then demonstrated that USP22 mediates CRC cell chemoresistance through the Wnt/β-catenin pathway and that reducing USP22 in CRC cells diminishes chemoresistance. Conclusions: Having established the crucial role of USP22 in CRC stemness and chemoresistance, this study suggests that USP22 may be an ideal genetic target in the treatment of chemoresistant CRC.

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“…Moreover, another recent study has demonstrated that disruption of the GSK-3β-USP22-KDM1A axis by tideglusib therapy suppresses glioma tumorigenesis and sensitizes intracranial GBM xenografts to TMZ leading to an improved mouse survival suggesting an inhibition of GSK-3 as a potential therapeutic approach for the treatment of human GBM (55). …”

Section: Development Of Gsk-3 Inhibitors For the Treatment Of Cancermentioning

confidence: 99%

Molecular Pathways: Revisiting Glycogen Synthase Kinase-3β as a Target for the Treatment of Cancer

Walz

Ugolkov

Chandra³

et al. 2017

Clinical Cancer Research

129

102

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Glycogen synthase kinase-3β (GSK-3β), a serine/threonine protein kinase, is a complex regulator of numerous cellular functions. GSK-3β is a unique kinase which is constitutively active in resting and non-stimulated cells. GSK-3β has been implicated in a wide range of diseases including neurodegeneration, inflammation and fibrosis, noninsulin-dependent diabetes mellitus, and cancer. It is a regulator of NF-κB-mediated survival of cancer cells, which provided a rationale for the development of GSK-3 inhibitors targeting malignant tumors. Recent studies, many of them reported over the past decade, have identified GSK-3β as a potential therapeutic target in at over 15 different types of cancer. Whereas only active GSK-3β is expressed in cancer cell nucleus, aberrant nuclear accumulation of GSK-3β has been identified as a hallmark of cancer cells in malignant tumors of different origin. This review focuses on the preclinical and clinical development of GSK-3 inhibitors, and the potential therapeutic impact of targeting GSK-3β in human cancer.

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Nuclear GSK3β promotes tumorigenesis by phosphorylating KDM1A and inducing its deubiquitylation by USP22

Cited by 132 publications

References 53 publications

m 6 A Demethylase ALKBH5 Maintains Tumorigenicity of Glioblastoma Stem-like Cells by Sustaining FOXM1 Expression and Cell Proliferation Program

m 6 A Demethylase ALKBH5 Maintains Tumorigenicity of Glioblastoma Stem-like Cells by Sustaining FOXM1 Expression and Cell Proliferation Program

Ubiquitin-Specific Peptidase 22 Contributes to Colorectal Cancer Stemness and Chemoresistance via Wnt/β-Catenin Pathway

Molecular Pathways: Revisiting Glycogen Synthase Kinase-3β as a Target for the Treatment of Cancer

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