2. Academic Validation
  3. DNA hypomethylator phenotype reprograms glutamatergic network in receptor tyrosine kinase gene-mutated glioblastoma

DNA hypomethylator phenotype reprograms glutamatergic network in receptor tyrosine kinase gene-mutated glioblastoma

  • Acta Neuropathol Commun. 2024 Mar 13;12(1):40. doi: 10.1186/s40478-024-01750-x.
Mio Harachi # 1 2,  Kenta Masui # 3,  Erika Shimizu 1,  Kumiko Murakami 1,  Hiromi Onizuka 1,  Yoshihiro Muragaki 4 5,  Takakazu Kawamata 4,  Hisako Nakayama 6,  Mariko Miyata 6,  Takashi Komori 7,  Webster K Cavenee 8,  Paul S Mischel 9,  Atsushi Kurata 1,  Noriyuki Shibata 1
Affiliations

Affiliations

  • 1 Department of Pathology, Tokyo Women's Medical University, Shinjuku, Tokyo, 162-8666, Japan.
  • 2 Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, 230-0045, Japan.
  • 3 Department of Pathology, Tokyo Women's Medical University, Shinjuku, Tokyo, 162-8666, Japan. [email protected].
  • 4 Department of Neurosurgery, Tokyo Women's Medical University, Shinjuku, Tokyo, 162-8666, Japan.
  • 5 Center for Advanced Medical Engineering Research and Development, Kobe University, Kobe, Hyogo, 650-0047, Japan.
  • 6 Department of Physiology, Tokyo Women's Medical University, Shinjuku, Tokyo, 162-8666, Japan.
  • 7 Department of Neuropathology, Tokyo Metropolitan Neurological Hospital, Musashinodai, Tokyo, 156-8506, Japan.
  • 8 Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA, 92093, USA.
  • 9 Department of Pathology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
  • # Contributed equally.
PMID: 38481314 DOI: 10.1186/s40478-024-01750-x
Abstract

DNA methylation is crucial for chromatin structure and gene expression and its aberrancies, including the global "hypomethylator phenotype", are associated with Cancer. Here we show that an underlying mechanism for this phenotype in the large proportion of the highly lethal brain tumor glioblastoma (GBM) carrying receptor tyrosine kinase gene mutations, involves the mechanistic target of rapamycin complex 2 (mTORC2), that is critical for growth factor signaling. In this scenario, mTORC2 suppresses the expression of the de novo DNA Methyltransferase (DNMT3A) thereby inducing genome-wide DNA hypomethylation. Mechanistically, mTORC2 facilitates a redistribution of EZH2 Histone Methyltransferase into the promoter region of DNMT3A, and epigenetically represses the expression of DNA Methyltransferase. Integrated analyses in both orthotopic mouse models and clinical GBM samples indicate that the DNA hypomethylator phenotype consistently reprograms a glutamate metabolism network, eventually driving GBM cell invasion and survival. These results nominate mTORC2 as a novel regulator of DNA hypomethylation in Cancer and an exploitable target against cancer-promoting Epigenetics.

Keywords

DNA hypomethylation; DNMT3A; EZH2; Glioblastoma; Glutamate metabolism; mTORC2.

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