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.epigenomics | glioblastoma | neoplastic stem cells G lioblastoma is the most common primary brain cancer and remains one of the deadliest of malignancies despite contemporary treatment strategies (1), with near-uniform fatality within 2 y of diagnosis (2, 3). There is growing evidence that the lethality of this tumor is driven by subpopulations of cells with properties of self-renewal and tumorigenicity (4)-that is, the capacity to generate phenocopies of the original tumor when transplanted (5, 6). How glioblastoma cells retain or gain tumorigenicity while the bulk of the tumor does not remains a fundamental question. Conceptualization of this phenomenon includes the elite and stochastic models (7). The elite model states that restricted cell subpopulations harbor intrinsic tumorigenic properties that cannot be acquired once lost. The stochastic model, on the other hand, presupposes that all cells within a population are intrinsically comparable in their ability to spontaneously acquire or lose tumorigenicity.Epigenetic alterations are stable, long-term changes in cellular phenotype that are not due to variations in DNA sequence (8). One means by which epigenetic alterations impact cell phenotype involves modulation of transcriptional activity via histone modification (9). Here we demonstrate that glioblastoma tumorigenicity is best conceptualized by a hybrid elite-stochastic model governed by histone modification through the lysine-specific demethylase 1 (LSD1; aka KDM1A) (10). This modification, in turn, influences the expression of key transcription factors required to reprogram glioblastoma cells into a stem-like state, including avian myelocytomatosis viral oncogene homolog (MYC) (11), oligodendrocyte lineage transcri...

AdipoR1-mediated miR-3908 inhibits glioblastoma tumorigenicity through downregulation of STAT2 associated with the AMPK/SIRT1 pathway

“…GBM is the primary and deadliest malignancy of the brain and extremely common (30)(31)(32) with near highest fatality in two years after diagnosis (33,34). The cellular capacity, which reconstitute the tumor entirely, and tumorigenicity of cell subpopulations are the major reasons of therapeutic failure (31).…”

“…The cellular capacity, which reconstitute the tumor entirely, and tumorigenicity of cell subpopulations are the major reasons of therapeutic failure (31). Growing evidence indicates cell subpopulations of GBM induce its lethality based on the properties of its tumorigenicity and self-renewal (35).…”

“…It demonstrated that the primary tumor could generate phenocopies (36,37). Key transcription factors could be regulated with epigenetic modifications and then control transformation between therapeutic developments and tumorigenic states of GBM (31). .…”

CNS Anticancer Drug Discovery and Development: 2016 conference insights

“…Based on studies of the GBM tumor microenvironment, it can be shown that GBM cells express cell surface molecules that suppress the immunologic function of microglia, while microglia reciprocally secrete specific cytokines to stimulate GBM growth [32]. These interactions are mediated in-part through secreted microvesicles, while PI3K γ regulates recruitment and protumor properties in microglia, suggesting a targetable strategy through inhibition of PI3K γ.…”

The role of micro-RNA in the regulation of signal pathways in gliomas

“…Важно, что недостаток KDM1A увеличивает H3K4-триметилирование локуса онкогена MYC, активирующее его экспрессию при глиобластоме, и MYC-опосредованное изменение экспрессии транскрипционных факторов OLIG2 и SOX2 [87].…”