Abstract LB-58: Role of mitochondrial ROS in activation of glioma stem cells and promotion of cancer development

Glioblastoma (GBM) is the most lethal brain tumor containing glioma stem cells (GSCs) that promote malignant growth and therapeutic resistance. The self-renewal and tumorigenic potential of GSCs are maintained by core stem cell transcription factors including SOX2. Defining the posttranslational regulation of SOX2 may offer new insights into GSC biology and potential therapeutic opportunity. Here, we discover that HAUSP stabilizes SOX2 through deubiquitination to maintain GSC self-renewal and tumorigenic potential. HAUSP is preferentially expressed in GSCs in perivascular niches in GBMs. Disrupting HAUSP by shRNA or its inhibitor P22077 promoted SOX2 degradation, induced GSC differentiation, impaired GSC tumorigenic potential, and suppressed GBM tumor growth. Importantly, pharmacological inhibition of HAUSP synergized with radiation to inhibit GBM growth and extended animal survival, indicating that targeting HAUSP may overcome GSC-mediated radioresistance. Our findings reveal an unappreciated crucial role of HAUSP in the GSC maintenance and provide a promising target for developing effective anti-GSC therapeutics to improve GBM treatment.

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CSIG-27. PRC2-INDEPENDENT FUNCTION OF EZH2/HP1BP3 COMPLEX IN GLIOMA STEM CELLS

Neuro-Oncology ◽

10.1093/neuonc/noz175.197 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi49-vi50

Author(s):

Junxia Zhang ◽

Tianfu Yu ◽

Ning Liu

Keyword(s):

Stem Cells ◽

Transcriptional Repression ◽

Glioma Stem Cells ◽

Independent Function ◽

Set Domain ◽

Heterochromatin Protein 1 ◽

Heterochromatin Protein ◽

Histone Lysine Methyltransferase ◽

Lysine Methyltransferase

Abstract Glioblastoma (GBM) displays cellular and genetical heterogeneity harboring a subpopulation of glioma stem cells (GSCs). Enhancer of zeste homolog 2 (EZH2), a histone lysine methyltransferase, is the core subunit of the polycomb repressor 2 (PRC2) complex, mediates gene transcriptional repression in both normal and tumor stem cells. An oncogenic role of EZH2 as a PRC2-dependent transcriptional silencer is well established; however, non-canonical functions of EZH2 are incompletely understood. Here we found a novel oncogenic mechanism for EZH2 in a PRC2-indenpend way in GSCs. Using HPLC-MS/MS and IP assay, EZH2 bound to HP1BP3 (heterochromatin protein 1 binding protein 3), a heterochromatin-related protein, with its pre-SET domain. Overexpression of H1P3B3 enhanced the proliferation, self-renewal and temozolomide (TMZ) resistance of GBM cells. Intriguingly, H1PBP3 was up-regulated in high grade gliomas with proneural (PN) subtypes and had a high predictive value on prognosis in patients with PN gliomas. Furthermore, EZH2 and HP1BP3 co-activated the expression of WNT7B by blocking the methylation of H3K9, thereby increasing TMZ resistance and tumorigenicity of glioblastoma cells. Interestingly, inhibition of WNT7B autocrine via LGK974, a specific porcupine inhibitor, effectively reversed the TMZ resistance of both GSCs and GBM glioma cells expressing HP1BP3. Hence, targeting the PRC2-independent function of EZH2 is an effective approach to enhance the efficacy of treating GBM.

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Abstract 347: The role of the epithelial-mesenchymal transition in the maintenance of stemness in neural and glioma stem cells

10.1158/1538-7445.am2012-347 ◽

2012 ◽

Author(s):

Nestor Fernandez ◽

Megan Wu ◽

Sunit Das

Keyword(s):

Stem Cells ◽

Epithelial Mesenchymal Transition ◽

Glioma Stem Cells ◽

Mesenchymal Transition

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TMIC-01. THE DYSTROGLYCAN RECEPTOR MAINTAINS GLIOMA STEM CELLS IN THE VASCULAR NICHE

Neuro-Oncology ◽

10.1093/neuonc/noz175.1035 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi247-vi247

Author(s):

Bryan Day ◽

Justin Lathia ◽

Zara Bruce ◽

Kathleen Ensbey ◽

Yi Chieh Lim ◽

...

Keyword(s):

Stem Cells ◽

Critical Factor ◽

Glioma Stem Cells ◽

Structural Element ◽

Α Subunit ◽

Vascular Niche ◽

Cns Neoplasms ◽

Tumour Initiation

Abstract Glioblastomas (GBMs) are malignant central nervous system (CNS) neoplasms with a very poor prognosis. They display cellular hierarchies containing self-renewing tumourigenic glioma stem cells (GSCs) in a complex heterogeneous microenvironment. One proposed GSC niche is the extracellular matrix (ECM)-rich perivascular bed of the tumour. Here, we report that the ECM binding alpha (α) subunit of the dystroglycan (DG) receptor is expressed and functionally glycosylated on GSCs residing in the vascular niche. Glycosylated αDG is also expressed highly on the most aggressive mesenchymal-like GBM tumour tissue. Furthermore, we found that DG acts to maintain a de-differentiated stem cell-like phenotype via tight control of MAPK activation. Antibody-based blockade of αDG induces robust ERK-mediated differentiation leading to reduced GSC potential. DG was shown to be required for tumour initiation, with constitutive loss significantly delaying or preventing tumourigenic potential in-vivo. These findings reveal a central role of the DG receptor not only as a structural element but also as a critical factor in the maintenance of GSCs in the GBM vascular niche.

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