Hgg-25. Targeting the Epigenetic Modifier Hmga2 in Dipg and High Grade Gliomas Inhibits Proliferation, Invasion and Tumorigenicity
Year: 2019
Type: conference-abstract
Abstract: Diffuse intrinsic pontine glioma (DIPG) and glioblastoma (GBM) are infiltrative and lethal brain tumors. Identifying and targeting novel molecular markers is urgently needed. Although DIPG and GBM have different epigenetic drivers, we found increased expression of an epigenetic modifier and stem cell factor HMGA2 in a subset of both tumors and multiple patient-derived cell lines by immunohistochemistry and western blotting. HMGA2 is a DNA minor-groove binding protein that regulates transcription in normal and cancer stem cells. We hypothesized that HMGA2 contributes to high grade glioma tumorigenicity by altering the transcription of many genes. Lentiviral short hairpin RNA (shRNA)-mediated reduction of HMGA2 in DIPG and GBM cells significantly reduced invasion (transwell assay) and proliferation (BrdU incorporation), and increased apoptosis (cleaved caspase-3, shHMGA2 vs. shControl, P < 0.01). Mice bearing orthotopic GBM xenograft cells transduced with HMGA2 shRNA lived longer (median survival = 108 days) compared to control shRNA (67.5 days, P < 0.0001 by log-rank analysis). Pharmacological inhibition of HMGA proteins using the DNA minor-groove binding drug quinacrine caused dose-dependent reduction in proliferation (BrdU), and increase in apoptosis (cleaved caspase-3) of DIPG neurospheres (P<0.01). Quinacrine had no effect on growth of normal hindbrain cells. Quinacrine has a well-known safety profile, is brain penetrable and we can achieve therapeutically efficacious micromolar concentration of quinacrine in mouse and zebrafish brain after oral administration without overt toxicity. To investigate the mechanism of HMGA2-mediated malignancy, we discovered high levels of CD44 (a known mediator of invasion and stemness) that correlated with high HMGA2 expression in DIPG and GBM tumors. Suppression of HMGA2 led to decreased CD44 protein expression. Knockdown of CD44 in HMGA2-high glioma neurospheres reduced invasion (P<0.01). Our results identify HMGA2 as a potential therapeutic target and suggest that minor groove binding agents like quinacrine may be effective therapeutics for pediatric high-grade gliomas.
Source: Neuro-Oncology
Institution: Johns Hopkins University
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2940804654