EPIG-02DYNAMIC EPIGENETIC MODULATION OF GLIOBLASTOMA TUMORIGENICITY BY INHIBITION OF LYSINE-SPECIFIC DEMETHYLASE 1 (LSD1)
| Autor: | Chang-Hyuk Kwon, Shan Zhu, Valya Ramakrishnan, Hideyuki Saya, Scott R. VandenBerg, Kaya Zhu, Wei Hua, David D. Gonda, Deepa Kushwaha, Oltea Sampetrean, Ichiro Nakano, Clark C. Chen, Masayuki Nitta, Hiroko Matsui, Donald P. Pizzo, Olivier Harismendy, Jie Li, Ying Mao, Dmitry Merzon, David Kozono |
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| Rok vydání: | 2015 |
| Předmět: | |
| Zdroj: | Neuro-Oncology. 17:v86.2-v86 |
| ISSN: | 1523-5866 1522-8517 |
| DOI: | 10.1093/neuonc/nov214.02 |
| Popis: | Glioblastoma is one of the most devastating of human cancers, with near-uniform fatality within two years of diagnosis. Therapeutic failure is thought to be related to small subpopulation of cells that exhibit the properties of self-renewal and tumorigenicity. It remains unclear whether tumorigenicity exists as a static property of a few cells (“elite” model) or as a dynamically acquired property (“stochastic” model). We used tumor-sphere and xenograft formation as assays for tumorigenicity and examined subclones isolated from established and primary patient-derived glioblastoma (PDX) lines. In multiple PDX lines, glioblastoma subclones that are isogenic (within the limits of the current DNA sequencing technology) nevertheless display varying tumorigenicity. Moreover, the property can be gained or lost at low frequencies. The results indicated that while glioblastoma tumorigenicity largely conforms to the “elite” model, there is dynamic interplay between tumorgenic and non-tumorgenic cell states. Using independent Genetically Engineered Murine Models (GEMMs) of glioblastoma, PDX glioblastoma models, and single cell analysis of clinical glioblastoma specimens, we demonstrate that these dynamic transitions are governed by epigenetic reprogramming through the lysine-specific demethylase 1 (LSD1). LSD1 depletion increases H3K4me3 accumulation at the MYC locus, which elevates MYC expression. MYC, in turn, regulates OLIG2, SOX2 and POU3F2, a core set of transcription factors required for reprogramming glioblastoma cells into stem-like states. Altered tumorgenic potential was not accompanied by a change in the molecular subtype (as defined by the TCGA) and was therefore not related to subtype plasticity. Importantly, complete inhibition or silencing of LSD1 led to suppression of MYC expression and glioblastoma tumorigenicity in vitro and in vivo. However, partial inhibition of LSD1 lead to epigenetic reprogramming resulting in heritable increase MYC expression and glioblastoma tumorigenicity. Our model suggests epigenetic regulation of key transcription factors governs transitions between tumorigenic states and provides a framework for glioblastoma therapeutic development. |
| Databáze: | OpenAIRE |
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