Dynamic epigenetic regulation of glioblastoma tumorigenicity through LSD1 modulation of MYC expression

David Kozono, Jie Li, Masayuki Nitta, Oltea Sampetrean, David Gonda, Deepa S. Kushwaha, Dmitry Merzon, Valya Ramakrishnan, Shan Zhu, Kaya Zhu, Hiroko Matsui, Olivier Harismendy, Wei Hua, Ying Mao, Chang Hyuk Kwon, Hideyuki Saya, Ichiro Nakano, Donald P. Pizzo, Scott R. Van Den Berg, Clark C. Chen

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29 Citations (Scopus)

Abstract

The available evidence suggests that the lethality of glioblastoma is driven by small subpopulations of cells that self-renew and exhibit tumorigenicity. It remains unclear whether tumorigenicity exists as a static property of a few cells or as a dynamically acquired property. We used tumor-sphere and xenograft formation as assays for tumorigenicity and examined subclones isolated from established and primary glioblastoma lines. Our results indicate that glioblastoma tumorigenicity is largely deterministic, yet the property can be acquired spontaneously at low frequencies. Further, these dynamic transitions are governed by epigenetic reprogramming through the lysine-specific demethylase 1 (LSD1). LSD depletion increases trimethylation of histone 3 lysine 4 at the avian myelocytomatosis viral oncogene homolog (MYC) locus, which elevates MYC expression. MYC, in turn, regulates oligodendrocyte lineage transcription factor 2(OLIG2), SRY (sex determining region Y)-box 2(SOX2), and POU class 3 homeobox 2 (POU3F2), a core set of transcription factors required for reprogramming glioblastoma cells into stem-like states. Our model suggests epigenetic regulation of key transcription factors governs transitions between tumorigenic states and provides a framework for glioblastoma therapeutic development.

Original languageEnglish
Pages (from-to)E4055-E4064
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number30
DOIs
Publication statusPublished - 2015 Jul 28

Keywords

  • Epigenomics
  • Glioblastoma
  • Neoplastic stem cells

ASJC Scopus subject areas

  • General

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    Kozono, D., Li, J., Nitta, M., Sampetrean, O., Gonda, D., Kushwaha, D. S., Merzon, D., Ramakrishnan, V., Zhu, S., Zhu, K., Matsui, H., Harismendy, O., Hua, W., Mao, Y., Kwon, C. H., Saya, H., Nakano, I., Pizzo, D. P., Van Den Berg, S. R., & Chen, C. C. (2015). Dynamic epigenetic regulation of glioblastoma tumorigenicity through LSD1 modulation of MYC expression. Proceedings of the National Academy of Sciences of the United States of America, 112(30), E4055-E4064. https://doi.org/10.1073/pnas.1501967112