title: The CRISPR/Cas9 system targeting EGFR exon 17 abrogates NF-κB activation via epigenetic modulation of UBXN1 in EGFRwt/vIII glioma cells.
abstract: Worldwide, glioblastoma (GBM) is the most lethal and frequent intracranial tumor. Despite decades of study, the overall survival of GBM patients remains unchanged. epidermal growth factor receptor (EGFR) amplification and gene mutation are thought to be negatively correlated with prognosis. In this study, we used proteomics to determine that UBXN1 is a negative downstream regulator of the EGFR mutation vIII (EGFRvIII). Via bioinformatics analysis, we found that UBXN1 is a factor that can improve glioma patients' overall survival time. We also determined that the down-regulation of UBXN1 is mediated by the upregulation of H3K27me3 in the presence of EGFRvIII. Because NF-κB can be negatively regulated by UBXN1, we believe that EGFRwt/vIII activates NF-κB by suppressing UBXN1 expression. Importantly, we used the latest genomic editing tool, CRISPR/Cas9, to knockout EGFRwt/vIII on exon 17 and further proved that UBXN1 is negatively regulated by EGFRwt/vIII. Furthermore, knockout of EGFR/EGFRvIII could benefit GBM in vitro and in vivo, indicating that CRISPR/Cas9 is a promising therapeutic strategy for both EGFR amplification and EGFR mutation-bearing patients.
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Lab of Neuro-oncology, Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin 300052, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Huang
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Lab of Neuro-oncology, Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin 300052, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Lab of Neuro-oncology, Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin 300052, China.
authors.forename: Qi-Xue
authors.initials: QX
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Lab of Neuro-oncology, Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin 300052, China.
authors.forename: Yan-Sheng
authors.initials: YS
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, The Hospital Affiliated with Hebei University, Baoding 071000, China.
authors.forename: Chuan
authors.initials: C
authors.lastname: Fang
authors.affiliation: College of Fundamental Medicine, Hebei University, Baoding 071000, China.
authors.forename: Yan-Li
authors.initials: YL
authors.lastname: Tan
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Lab of Neuro-oncology, Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin 300052, China.
authors.forename: Jian-Wei
authors.initials: JW
authors.lastname: Wei
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Lab of Neuro-oncology, Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin 300052, China.
authors.forename: Yun-Fei
authors.initials: YF
authors.lastname: Wang
authors.affiliation: ProteinT(Tianjin) Biotechnology Co., Ltd, Tianjin 300457, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Lab of Neuro-oncology, Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin 300052, China.
authors.forename: Jun-Hu
authors.initials: JH
authors.lastname: Zhou
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Lab of Neuro-oncology, Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin 300052, China.
authors.forename: Bing-Cong
authors.initials: BC
authors.lastname: Zhou
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Lab of Neuro-oncology, Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin 300052, China.
authors.forename: Kai-Kai
authors.initials: KK
authors.lastname: Yi
authors.affiliation: Department of Neurosurgery, Qilu Hospital of Shandong University, Brain Science Research Institute, Shandong University, China.
authors.forename: Kai-Liang
authors.initials: KL
authors.lastname: Zhang
authors.affiliation: ProteinT(Tianjin) Biotechnology Co., Ltd, Tianjin 300457, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Lab of Neuro-oncology, Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin 300052, China. Electronic address: kang97061@tmu.edu.cn.
authors.forename: Chun-Sheng
authors.initials: CS
authors.lastname: Kang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D064112:Clustered Regularly Interspaced Short Palindromic Repeats / Q000235:genetics*; D057890:Epigenomics; D066246:ErbB Receptors / Q000378:metabolism; D005091:Exons; D005260:Female; D005910:Glioma / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016328:NF-kappa B; C504037:UBXN1 protein, human; D066246:ErbB Receptors
keywords: CRISPR/Cas9; EGFR/EGFRvIII; Glioblastoma; NF-κB; UBXN1