Targeting NEK2 attenuates glioblastoma growth and radioresistance by destabilizing histone methyltransferase EZH2

Wang, Jia; Peng, Cheng; Pavlyukov, Marat S.; Yu, Hai; Zhang, Zhuo; Kim, Sung Hak; Minata, Mutsuko; Mohyeldin, Ahmed; Xie, Wei; Chen, Dongquan; Goidts, Violaine; Frett, Brendan; Hu, Wenhao; Li, Hongyu; Shin, Yong Jae; Lee, Yeri; Nam, Do Hyun; Kornblum, Harley I.; Wang, Maode; Nakano, ﻿Ichiro

doi:10.1172/jci89092

Cited by 79 publications

(87 citation statements)

References 43 publications

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“…To thoroughly explore the potential prognostic biomarkers for glioma, kinome‐wide hierarchical bi‐clustering was performed using previously published microarray databases related to TMZ resistance, World Health Organization (WHO) grade, and radiotherapeutic resistance (Tso et al, 2015; Mao et al, 2015 and Wang et al, 2017). The differentially expressed genes were sorted by their fold changes (Figure A‐C, and Tables S1‐S3).…”

Section: Resultsmentioning

confidence: 99%

“…The differentially expressed genes were sorted by their fold changes (Figure A‐C, and Tables S1‐S3). The genes that were more than 1.5‐fold upregulated were selected from Tso et al and Mao et al Moreover, genes that were upregulated by 0.2‐fold were extracted from the Wang et al database. The overlapping genes from those three gene lists are summarized.…”

Section: Resultsmentioning

confidence: 99%

“…GIS was used to analyze the expression of TRIB2 and MAP3K1 as previously described . The immunoreactivity score was calculated according to the following equation: immunoreactivity score = positive cell score × staining intensity score.…”

Section: Methodsmentioning

confidence: 99%

“…Increasing data have shown that kinase‐dependent activation of tumorigenesis and therapeutic resistance is one of the major causes for GBM tumor recurrence, indicating that aberrant enhanced kinase activity could be a potential predictive biomarker for GBM . In this study, to further investigate prognostic biomarkers for glioma, kinome‐wide screening was first performed with 3 GEO datasets (Mao et al, 2015, Tso et al, 2015, and Wang et al, 2017). TRIB2 and MAP3K1 were identified as genes that are correlated with the pathology and survival of glioma.…”

Section: Introductionmentioning

confidence: 99%

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Combined elevation of TRIB2 and MAP3K1 indicates poor prognosis and chemoresistance to temozolomide in glioblastoma

et al. 2019

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Introduction Glioblastoma (GBM) is the most lethal primary malignant brain tumor in adults with poor survival due to acquired therapeutic resistance and rapid recurrence. Currently, the standard clinical strategy for glioma includes maximum surgical resection, radiotherapy, and temozolomide (TMZ) chemotherapy; however, the median survival of patients with GBM remains poor despite these comprehensive therapies. Therefore, the identification of new prognostic biomarkers is urgently needed to evaluate the malignancy and long‐term outcome of glioma. Aims To further investigate prognostic biomarkers and potential therapeutic targets for GBM. Results In this study, we identified tribbles pseudokinase 2 (TRIB2) as one of the genes that is most correlated with pathological classification, radioresistance, and TMZ resistance in glioma. Additionally, the expression of mitogen‐activated protein kinase kinase kinase 1 (MAP3K1) showed a strong correlation with TRIB2. Moreover, a combined increase in TRIB2 and MAP3K1 was observed in GBM and indicated a poor prognosis of patients with glioma. Finally, enriched TRIB2 expression and MAP3K1 expression were shown to be associated with resistance to TMZ and radiotherapy. Conclusion Combined elevation of TRIB2 and MAP3K1 could be novel prognostic biomarkers and potential therapeutic targets to evaluate the malignancy and long‐term outcomes of GBM.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Combined elevation of TRIB2 and MAP3K1 indicates poor prognosis and chemoresistance to temozolomide in glioblastoma

et al. 2019

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“…In vivo xenograft model was performed by using 6‐week‐old female nude mice. Corresponding GBM cell (pretransfected with shNT, shCXCL1#1 and shCXCL1#2) was suspended and diluted to the density of 1 × 10 5 cells in 2 uL PBS then injected into the nude mice brains as described previously . Each group of treatment consists of five mice, and they were monitored unless the following symptoms came out: arched back, unsteady gait, more than 10% bodyweight loss, or leg paralysis.…”

Section: Methodsmentioning

confidence: 99%

Elevation of CXCL1 indicates poor prognosis and radioresistance by inducing mesenchymal transition in glioblastoma

Wahafu

Zuo

et al. 2020

CNS Neurosci Ther

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Introduction Glioblastoma (GBM) is identified as a lethal malignant tumor derived from the nervous system. Despite the standard clinical strategy including maximum surgical resection, temozolomide (TMZ) chemotherapy, and radiotherapy, the median survival of GBM patients remains <15 months. Accumulating evidence indicates that rapid‐acquired radioresistance is one of the most common reasons for GBM recurrence. Therefore, developing novel therapeutic targets for radioresistant GBM could yield long‐term cures. Aims To investigate the functional role of CXCL1 in the acquired radioresistance and identify the molecular pathway correlated to CXCL1. Results In this study, we identified that CXCL1 is highly expressed in GBM and the elevation of CXCL1 is involved in radioresistance and poor prognosis in GBM patients. Additionally, silencing CXCL1 attenuated the proliferation and radioresistance of GBM cells. Furthermore, we demonstrated that CXCL1‐overexpression induced radioresistance through mesenchymal transition of GBM via the activation of nuclear factor‐kappa B (NF‐κB) signaling. Conclusion CXCL1 was highly enriched in GBM and positively correlated with poor prognosis in GBM patients. Additionally, elevated CXCL1 induced radioresistance in GBM through regulation of NF‐κB signaling by promoting mesenchymal transition in GBM.

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Genetic Aberrations and Interaction of NEK2 and TP53 Accelerate Aggressiveness of Multiple Myeloma

Feng

Guo

et al. 2022

Advanced Science

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It has been previously shown that (never in mitosis gene A)‐related kinase 2 (NEK2) is upregulated in multiple myeloma (MM) and contributes to drug resistance. However, the mechanisms behind this upregulation remain poorly understood. In this study, it is found that amplification of NEK2 and hypermethylation of distal CpG islands in its promoter correlate strongly with increased NEK2 expression. Patients with NEK2 amplification have a poor rate of survival and often exhibit TP53 deletion, which is an independent prognostic factor in MM. This combination of TP53 knockout and NEK2 overexpression induces asymmetric mitosis, proliferation, drug resistance, and tumorigenic behaviors in MM in vitro and in vivo. In contrast, delivery of wild type p53 and suppression of NEK2 in TP53−/− MM cell lines inhibit tumor formation and enhance the effect of Bortezomib against MM. It is also discovered that inactivating p53 elevates NEK2 expression genetically by inducing NEK2 amplification, transcriptionally by increased activity of cell cycle‐related genes like E2F8 and epigenetically by upregulating DNA methyltransferases. Dual defects of TP53 and NEK2 may define patients with the poorest outcomes in MM with p53 inactivation, and NEK2 may serve as a novel therapeutic target in aggressive MM with p53 abnormalities.

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Targeting NEK2 attenuates glioblastoma growth and radioresistance by destabilizing histone methyltransferase EZH2

Cited by 79 publications

References 43 publications

Combined elevation of TRIB2 and MAP3K1 indicates poor prognosis and chemoresistance to temozolomide in glioblastoma

Combined elevation of TRIB2 and MAP3K1 indicates poor prognosis and chemoresistance to temozolomide in glioblastoma

Elevation of CXCL1 indicates poor prognosis and radioresistance by inducing mesenchymal transition in glioblastoma

Genetic Aberrations and Interaction of NEK2 and TP53 Accelerate Aggressiveness of Multiple Myeloma

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