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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2015-07, Vol.112 (30), p.E4055-E4064
• Main Authors: Kozono, David, 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. VandenBerg, Clark C. Chen
• Format: Article
• Language: English
• Subjects: adults; Animals; Biological Sciences; brain; Brain Neoplasms - metabolism; Cell Line, Tumor; Cell Transformation, Neoplastic; Cells; Epigenesis, Genetic; Epigenetics; epigenomics; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Silencing; glioblastoma; Glioblastoma - metabolism; Histone Demethylases - metabolism; Humans; Male; Mice; Mice, Inbred C57BL; Neoplasm Transplantation; neoplasms; Neoplasms - metabolism; neoplastic stem cells; PNAS Plus; Proto-Oncogene Proteins c-myc - metabolism; Stochastic Processes; Subpopulations; transcription factors; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1501967112

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. Glioblastoma is the most common type of adult brain cancer, with near-uniform fatality within 2 y of diagnosis. Therapeutic failure is thought to be related to small subpopulations of cells that exhibit tumorigenicity, the cellular capacity to reconstitute the entire tumor mass. One fundamental issue is whether tumorigenicity exists within a static subpopulation of cells or whether the capacity is stochastically acquired. We provide evidence that tumorigenicity is a cellular property that is durable yet undergoes low-frequency stochastic changes. We showed that these changes are driven by lysine-specific demethylase 1 (LSD1)-mediated epigenetic (heritable non-DNA sequence-altering) modifications that impact expression of key transcription factors, which in turn govern transitions between tumorigenic states. These findings harbor implications for glioblastoma therapeutic development.