SMURF2 phosphorylation at Thr249 modifies glioma stemness and tumorigenicity by regulating TGF-β receptor stability

Hiraiwa, Manami; Fukasawa, Kazuya; Iezaki, Takashi; Sabit, Hemragul; Horie, Tetsuhiro; Tokumura, Kazuya; Iwahashi, Sayuki; Murata, Misato; Kobayashi, Masaki; Suzuki, Akane; Park, Gyujin; Kaneda, Katsuyuki; Todo, Tomoki; Hirao, Atsushi; Nakada, Mitsutoshi; Hinoi, Eiichi

doi:10.1038/s42003-021-02950-0

Cited by 14 publications

(8 citation statements)

References 50 publications

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“…Recently, we demonstrated that phosphorylation of the c-Myc axis by CDK8 and the extracellular signal regulated kinase 5/signal transducer and activator of transcription 3 axis by mitogen-activated protein kinase 5 controls the stemness and tumorigenicity of GSCs, contributing to GBM tumorigenesis (41). In addition, ubiquitination of the transforming growth factor-β receptor/R-Smad axis by Smad ubiquitin regulatory factor 2, an E3 ubiquitin ligase, controls the properties of GSCs and GBM malignancy (42). Moreover, methylation of regulator of chromosome condensation 1 by protein arginine methyltransferase 6 regulates tumorigenicity and radiation response of GSCs (43).…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics identification of potential protein glycosylation genes associated with glioma stem cell signature

Tokumura

Sadamori

Yoshimoto

et al. 2023

Preprint

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Glioma stem cells (GSCs) contribute to the pathogenesis of glioblastoma (GBM), which is the most malignant form of glioma. The implications and underlying mechanisms of protein glycosylation in GSC phenotypes and GBM malignancy are not fully understood. In this study, we aimed to investigate the implication of protein glycosylation and the corresponding candidate genes on the stem cell properties of GSCs and poor clinical outcomes in GBM, using single-cell RNA sequencing and bulk RNA sequencing datasets of clinical GBM specimens deposited in the Gene Expression Omnibus database, in addition to The Cancer Genome Atlas and the Chinese Glioma Genome Atlas databases of patients with glioma. We demonstrated that N-linked glycosylation was significantly associated with GSC properties and the prognosis of GBM by conducting integrated bioinformatics analyses of clinical specimens. N-linked glycosylation was associated with the glioma grade, molecular biomarkers, and molecular subtypes. The expression levels of the asparagine-linked glycosylation (ALG) enzyme family, which is essential for the early steps in the biosynthesis of N-glycans, were prominently associated with GSC properties and poor survival in patients with GBM with high stem-cell properties. Finally, the oxidative phosphorylation (OXPHOS) pathway was primarily enriched in GSCs with a high expression of the ALG enzyme family. Collectively, these findings uncover a pivotal role for N-linked glycosylation in the regulation of GSC phenotypes and GBM malignancy through, possibly in part, the ALG-OXPHOS axis, thereby revealing a potential target for GSC-directed therapy.

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Section: Discussionmentioning

confidence: 99%

Bioinformatics identification of potential protein glycosylation genes associated with glioma stem cell signature

Tokumura

Sadamori

Yoshimoto

et al. 2023

Preprint

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“…Previously, frequent expression of ZNF165 has been reported in various cells [ 3 , 5 , 6 , 8 , 9 ]. The ZNF165, by directly inactivating the expression of negative feedback pathway regulators: SMURF2 [ 13 ], SMAD7 [ 14 ], and PMEPA1 [ 15 ], promotes the unrestrained activation of transforming growth factor β (TGF β ) signaling, which is required for the survival of triple-negative breast cancer cells in vitro and in vivo [ 7 , 8 ]. In this study, possible downstream pathways and factors that might be affected by ZNF165 were first analyzed; the tryptophan signaling pathway factors particularly CYP1A1 were downregulated after knocking down ZNF165 in HCC cells.…”

Section: Discussionmentioning

confidence: 99%

ZNF165 Is Involved in the Regulation of Immune Microenvironment and Promoting the Proliferation and Migration of Hepatocellular Carcinoma by AhR/CYP1A1

Liu

Zhou

Dong

et al. 2022

Journal of Immunology Research

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The strong tumorigenic capacity and treatment resistance made hepatocellular carcinoma (HCC) a huge threat to public health. ZNF165, the kruppel family of zinc-finger-containing transcription factors, is expressed in HCC; however, its specific role in HCC and the molecular mechanism are yet to be elucidated. In this study, we observed that ZNF165 was overexpressed in liver cancer tissues and the immune microenvironment; higher ZNF165 expression was correlated with lower overall survival in liver cancer patients. The ZNF165 knockdown in Bel7402 cells revealed the impairment of the tryptophan/kynurenine/AhR/CYP1A1 axis. Moreover, the knockdown of CYP1A1 significantly inhibited the proliferation and migration of HCC cells, and ZNF165 promoted the transcriptional activity of AhR by facilitating the nuclear translocation of CYP1A1. In conclusion, the present study argued that ZNF165 was highly expressed in liver tissues and the immune microenvironment. ZNF165 promoted the proliferation and migration of HCC cells by activating the tryptophan/kynurenine/AhR/CYP1A1 axis and promoting the expression of CYP1A1.

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“…Phosphorylation, as one of the most common protein modifications, regulates cell proliferation, differentiation, and signal transduction [ 56 ], and plays an important regulatory role in glioma. SMURF2 Thr249 phosphorylation regulated GBM aggressiveness through TGFBR-SMAD-SOX4 axis [ 57 ]. CircGLIS3 promoted invasion and tube formation of glioma through Ezrin T567 phosphorylation [ 58 ].…”

Section: Discussionmentioning

confidence: 99%

The mechanism of BUD13 m6A methylation mediated MBNL1-phosphorylation by CDK12 regulating the vasculogenic mimicry in glioblastoma cells

et al. 2022

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Vasculogenic mimicry (VM) is an endothelium-independent tumor microcirculation that provides adequate blood supply for tumor growth. The presence of VM greatly hinders the treatment of glioblastoma (GBM) with anti-angiogenic drugs. Therefore, targeting VM formation may be a feasible therapeutic strategy for GBM. The research aimed to evaluate the roles of BUD13, CDK12, MBNL1 in regulating VM formation of GBM. BUD13 and CDK12 were upregulated and MBNL1 was downregulated in GBM tissues and cells. Knockdown of BUD13, CDK12, or overexpression of MBNL1 inhibited GBM VM formation. METTL3 enhanced the stability of BUD13 mRNA and upregulated its expression through m6A methylation. BUD13 enhanced the stability of CDK12 mRNA and upregulated its expression. CDK12 phosphorylated MBNL1, thereby regulating VM formation of GBM. The simultaneous knockdown of BUD13, CDK12, and overexpression of MBNL1 reduced the volume of subcutaneously transplanted tumors in nude mice and prolonged the survival period. Thus, the BUD13/CDK12/MBNL1 axis plays a crucial role in regulating VM formation of GBM and provides a potential target for GBM therapy.

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SMURF2 phosphorylation at Thr249 modifies glioma stemness and tumorigenicity by regulating TGF-β receptor stability

Cited by 14 publications

References 50 publications

Bioinformatics identification of potential protein glycosylation genes associated with glioma stem cell signature

Bioinformatics identification of potential protein glycosylation genes associated with glioma stem cell signature

ZNF165 Is Involved in the Regulation of Immune Microenvironment and Promoting the Proliferation and Migration of Hepatocellular Carcinoma by AhR/CYP1A1

The mechanism of BUD13 m6A methylation mediated MBNL1-phosphorylation by CDK12 regulating the vasculogenic mimicry in glioblastoma cells

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