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  • Xu, AnDepartment of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, TX, Houston, United States (author)

Rewired m6A epitranscriptomic networks link mutant p53 to neoplastic transformation

  • Article/chapterEnglish2023

Publisher, publication year, extent ...

  • 2023-03-27
  • Springer Nature,2023
  • electronicrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:umu-206456
  • https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-206456URI
  • https://doi.org/10.1038/s41467-023-37398-9DOI

Supplementary language notes

  • Language:English
  • Summary in:English

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Classification

  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • N6-methyladenosine (m6A), one of the most prevalent mRNA modifications in eukaryotes, plays a critical role in modulating both biological and pathological processes. However, it is unknown whether mutant p53 neomorphic oncogenic functions exploit dysregulation of m6A epitranscriptomic networks. Here, we investigate Li-Fraumeni syndrome (LFS)-associated neoplastic transformation driven by mutant p53 in iPSC-derived astrocytes, the cell-of-origin of gliomas. We find that mutant p53 but not wild-type (WT) p53 physically interacts with SVIL to recruit the H3K4me3 methyltransferase MLL1 to activate the expression of m6A reader YTHDF2, culminating in an oncogenic phenotype. Aberrant YTHDF2 upregulation markedly hampers expression of multiple m6A-marked tumor-suppressing transcripts, including CDKN2B and SPOCK2, and induces oncogenic reprogramming. Mutant p53 neoplastic behaviors are significantly impaired by genetic depletion of YTHDF2 or by pharmacological inhibition using MLL1 complex inhibitors. Our study reveals how mutant p53 hijacks epigenetic and epitranscriptomic machinery to initiate gliomagenesis and suggests potential treatment strategies for LFS gliomas.

Subject headings and genre

Added entries (persons, corporate bodies, meetings, titles ...)

  • Liu, MoDepartment of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, TX, Houston, United States (author)
  • Huang, Mo-FanDepartment of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, TX, Houston, United States; University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, TX, Houston, United States (author)
  • Zhang, YangCollege of Science, Harbin Institute of Technology (Shenzhen), Guangdong, Shenzhen, China (author)
  • Hu, RuifengCenter for Precision Health, School of Biomedical Informatics, University of Texas Health Science Center at Houston, TX, Houston, United States (author)
  • Gingold, Julian A.Department of Obstetrics & Gynecology and Women's Health, Einstein/Montefiore Medical Center, NY, Bronx, United States (author)
  • Liu, YingDepartment of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, TX, Houston, United States (author)
  • Zhu, DandanDepartment of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, TX, Houston, United States (author)
  • Chien, Chian-ShiuDepartment of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan; College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan (author)
  • Wang, Wei-ChenInstitute of Molecular Biology, National Chung Hsing University, Taichung, Taiwan (author)
  • Liao, ZianVerna & Marrs McLean Department of Biochemistry & Molecular Biology and Therapeutic Innovation Center, Baylor College of Medicine, TX, Houston, United States (author)
  • Yuan, FeiVerna & Marrs McLean Department of Biochemistry & Molecular Biology and Therapeutic Innovation Center, Baylor College of Medicine, TX, Houston, United States (author)
  • Hsu, Chih-WeiDepartment of Molecular Physiology and Biophysics, Baylor College of Medicine, TX, Houston, United States (author)
  • Tu, JianDepartment of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, TX, Houston, United States (author)
  • Yu, YaoDepartment of Epidemiology, University of Texas MD Anderson Cancer Center, TX, Houston, United States (author)
  • Rosen, TaylorDepartment of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, TX, Houston, United States (author)
  • Xiong, FengDepartment of Biochemistry and Molecular Biology, McGovern Medical School, University of Texas Health Science Center at Houston, TX, Houston, United States (author)
  • Jia, PeilinCenter for Precision Health, School of Biomedical Informatics, University of Texas Health Science Center at Houston, TX, Houston, United States (author)
  • Yang, Yi-PingDepartment of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan; College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan (author)
  • Bazer, Danielle A.Department of Neurology, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY, United States (author)
  • Chen, Ya-WenDepartment of Otolaryngology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA; Institute for Airway Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA (author)
  • Li, WenboUniversity of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, TX, Houston, United States; Department of Biochemistry and Molecular Biology, McGovern Medical School, University of Texas Health Science Center at Houston, TX, Houston, United States (author)
  • Huff, Chad D.University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, TX, Houston, United States; Department of Epidemiology, University of Texas MD Anderson Cancer Center, TX, Houston, United States (author)
  • Zhu, Jay-JiguangDepartment of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, TX, Houston, United States (author)
  • Aguilo, Francesca,PhDUmeå universitet,Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM),Institutionen för molekylärbiologi (Medicinska fakulteten)(Swepub:umu)frag0008 (author)
  • Chiou, Shih-HwaDepartment of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan; College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan (author)
  • Boles, Nathan C.Neural Stem Cell Institute, NY, Rensselaer, United States (author)
  • Lai, Chien-ChenInstitute of Molecular Biology, National Chung Hsing University, Taichung, Taiwan; Graduate institute of Chinese Medical Science, China Medical University, Taichung, Taiwan; Ph.D. Program in Translational Medicine and Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan (author)
  • Hung, Mien-ChieGraduate Institute of Biomedical Sciences and Center for Molecular Medicine, Office of the President, China Medical University, Taichung, Taiwan; Department of Biotechnology, Asia University, Taichung, Taiwan (author)
  • Zhao, ZhongmingUniversity of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, TX, Houston, United States; Center for Precision Health, School of Biomedical Informatics, University of Texas Health Science Center at Houston, TX, Houston, United States (author)
  • Van Nostrand, Eric L.Verna & Marrs McLean Department of Biochemistry & Molecular Biology and Therapeutic Innovation Center, Baylor College of Medicine, TX, Houston, United States (author)
  • Zhao, RuiyingDepartment of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, TX, Houston, United States (author)
  • Lee, Dung-FangDepartment of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, TX, Houston, United States; University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, TX, Houston, United States; Center for Precision Health, School of Biomedical Informatics, University of Texas Health Science Center at Houston, TX, Houston, United States; Center for Stem Cell and Regenerative Medicine, Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Health Science Center at Houston, TX, Houston, United States (author)
  • Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, TX, Houston, United StatesDepartment of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, TX, Houston, United States; University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, TX, Houston, United States (creator_code:org_t)

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  • In:Nature Communications: Springer Nature14:12041-1723

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