title: Dynamic epigenetic regulation of glioblastoma tumorigenicity through LSD1 modulation of MYC expression.
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.
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215;
authors.forename: David
authors.initials: D
authors.lastname: Kozono
authors.affiliation: Division of Neurosurgery, University of California, San Diego, La Jolla, CA 92093;
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215;
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nitta
authors.affiliation: Division of Gene Regulation, Keio University School of Medicine, Tokyo 160-8582, Japan;
authors.forename: Oltea
authors.initials: O
authors.lastname: Sampetrean
authors.affiliation: Division of Neurosurgery, University of California, San Diego, La Jolla, CA 92093;
authors.forename: David
authors.initials: D
authors.lastname: Gonda
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215;
authors.forename: Deepa S
authors.initials: DS
authors.lastname: Kushwaha
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215;
authors.forename: Dmitry
authors.initials: D
authors.lastname: Merzon
authors.affiliation: Division of Neurosurgery, University of California, San Diego, La Jolla, CA 92093;
authors.forename: Valya
authors.initials: V
authors.lastname: Ramakrishnan
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215;
authors.forename: Shan
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215;
authors.forename: Kaya
authors.initials: K
authors.lastname: Zhu
authors.affiliation: Department of Pediatrics and Rady Children's Hospital, University of California, San Diego, La Jolla, CA 92093;
authors.forename: Hiroko
authors.initials: H
authors.lastname: Matsui
authors.affiliation: Department of Pediatrics and Rady Children's Hospital, University of California, San Diego, La Jolla, CA 92093;
authors.forename: Olivier
authors.initials: O
authors.lastname: Harismendy
authors.affiliation: Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China;
authors.forename: Wei
authors.initials: W
authors.lastname: Hua
authors.affiliation: Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China;
authors.forename: Ying
authors.initials: Y
authors.lastname: Mao
authors.affiliation: Department of Neurological Surgery, Ohio State University Medical Center, Columbus, OH 43210;
authors.forename: Chang-Hyuk
authors.initials: CH
authors.lastname: Kwon
authors.affiliation: Division of Gene Regulation, Keio University School of Medicine, Tokyo 160-8582, Japan;
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saya
authors.affiliation: Department of Neurological Surgery, Ohio State University Medical Center, Columbus, OH 43210;
authors.forename: Ichiro
authors.initials: I
authors.lastname: Nakano
authors.affiliation: Department of Pathology, University of California, San Diego, La Jolla, CA 92037.
authors.forename: Donald P
authors.initials: DP
authors.lastname: Pizzo
authors.affiliation: Department of Pathology, University of California, San Diego, La Jolla, CA 92037.
authors.forename: Scott R
authors.initials: SR
authors.lastname: VandenBerg
authors.affiliation: Division of Neurosurgery, University of California, San Diego, La Jolla, CA 92093; clarkchen@ucsd.edu.
authors.forename: Clark C
authors.initials: CC
authors.lastname: Chen
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D005909:Glioblastoma / Q000378:metabolism*; D056466:Histone Demethylases / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D013269:Stochastic Processes
chemical_list: D016271:Proto-Oncogene Proteins c-myc; D056466:Histone Demethylases; C504076:KDM1a protein, mouse; C495195:KDM1A protein, human
keywords: epigenomics; glioblastoma; neoplastic stem cells