2ⁿᵈ Edition of the Cancer R&D World Conference 2026

Abstract

Glioblastoma (GBM) is a highly malignant adult brain tumor characterized by extensive cellular, molecular, genetic, and epigenetic heterogeneity and remains associated with a dismal prognosis. This aggressive clinical behavior is attributed, in part, to the presence of brain tumor stem cells (BTSCs), a population of cancer stem-like cells characterized by enhanced self-renewal, multilineage differentiation potential, and tumor-initiating capacity. These properties contribute substantially to the biological complexity of GBM, therapeutic resistance, and tumor recurrence. In particular, BTSCs exhibit remarkable plasticity in response to epigenetic alterations, including aberrant histone methylation and acetylation resulting from dysregulation of key epigenetic regulators. Using complementary pharmacological inhibition and genetic loss- and gain-of-function approaches, we identified a functional coordination between histone deacetylase 2 (HDAC2) and components of the transforming growth factor-β (TGF-β) signaling pathway, including SMAD3 and SKI, which is essential for maintaining the growth and tumorigenic potential of patient-derived GBM BTSCs while suppressing neurodevelopmental transcriptional programs.

Inhibition of HDAC2 activity and disruption of the coordinated mechanisms regulated by the HDAC2-SMAD3-SKI axis are thus promising therapeutic approaches for targeting BTSCs. In a separate study, we demonstrated that tumor suppressor protein 4.1B, a negative regulator of protein arginine methyltransferase 3 (PRMT3), predicts GBM BTSC response to the PRMT3 chemical probe SGC707. Mechanistically, PRMT3 regulates the stability and subcellular localization of UHRF1, a key component of the DNA methylation machinery. The 4.1B–PRMT3–UHRF1/DNMT1 axis functions cooperatively to promote BTSC growth and maintenance. Thus, therapeutic targeting of PRMT3 or the UHRF1/DNMT1 axis may have particular therapeutic potential in GBMs characterized by low endogenous 4.1B expression. Collectively, these studies provide a mechanistic framework for understanding the interplay between epigenetic and molecular regulatory mechanisms in GBM. This bidirectional crosstalk contributes to the maintenance of the BTSC state and represents a potentially actionable vulnerability for therapeutic intervention.