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MOLECULAR MECHANISMS OF GLIOBLASTOMA PATHOGENESIS: TUSC2 DOWNREGULMOLECULAR MECHANISMS OF GLIOBLASTOMA PATHOGENESIS: TUSC2 DOWNREGULATION AND TGLI1 OVEREXPRESSION PROMOTE GLIOBLASTOMA DEVELOPMENT AND PROGRESSIONATION AND TGLI1 OVEREXPRESSION PROMOTE GLIOBLASTOMA DEVELOPMENT AND PROGRESSION

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title
MOLECULAR MECHANISMS OF GLIOBLASTOMA PATHOGENESIS: TUSC2 DOWNREGULMOLECULAR MECHANISMS OF GLIOBLASTOMA PATHOGENESIS: TUSC2 DOWNREGULATION AND TGLI1 OVEREXPRESSION PROMOTE GLIOBLASTOMA DEVELOPMENT AND PROGRESSIONATION AND TGLI1 OVEREXPRESSION PROMOTE GLIOBLASTOMA DEVELOPMENT AND PROGRESSION
author
Rimkus, Tadas K.
abstract
The molecular mechanisms underlying glioblastoma (GBM) development and progression have not been fully elucidated. Some of the earliest and most frequent genomic abnormalities in some cancers occur in distinct regions of chromosome 3p, suggesting these aberrations play a distinct role in the pathogenesis of these cancers. Tumor Suppressor Candidate 2 (TUSC2, also known as FUS1) is a putative tumor suppressor first characterized in lung cancer; however, its role in GBM remains poorly understood. The goal of my thesis study was therefore to determine the role of TUSC2 in gliomagenesis and GBM progression. We found that TUSC2 protein, but not mRNA, is decreased in GBM cells and patient samples compared to normal brain tissues. Decreased TUSC2 protein expression in GBM is due to shortened protein half-life, attributed to proteasome-dependent degradation. We discovered that the E3 ubiquitin ligase NEDD4 binds to and ubiquitinates TUSC2 at lysine 71 in GBM cells, mediating TUSC2 protein degradation. Re-expression of TUSC2 induced GBM apoptosis in vitro and in vivo and decreased GBM incidence and growth in an orthotopic GBM xenograft mouse study. Conversely, knockout of TUSC2 in TUSC2-expressing GBM cells promoted GBM growth in vitro and in vivo. Interestingly, previous studies have shown that NEDD4 acts as a novel regulator of the Hedgehog signaling. The GLI1 transcription factor functions as the nuclear effector of the Hedgehog signaling pathway and has been widely studied as a driver of oncogenesis, tumor growth, and cancer stem cell maintenance in a variety of cancers, including GBM. Truncated GLI1 (tGLI1), is a tumor-tissue specific, gain-of-function GLI1 transcription factor isoform that directly upregulates transcription of genes promoting a highly malignant GBM phenotype both in vitro and in vivo. We showed that tGLI1 expression promotes glioma stem cell function in mesenchymal GBM cells by upregulating CD44. Given the important role that TUSC2 loss and tGLI1 gain individually plays in GBM progression, we then asked whether there was a functional relationship between TUSC2 and tGLI1. Of note, whether TUSC2 and tGLI1 functionally cooperate has never been studied in any cancer or cell type. Our results showed that TUSC2 protein loss combined with high tGLI1 expression is a frequent event in GBM. TUSC2-downregulation and tGLI1-overexpression functionally cooperate to drive gliomagenesis and GBM progression partially by promoting glioma stem cell self-renewal and suppressing apoptosis. Collectively, studies conducted in my thesis projects provide novel insights into pathways that contribute to GBM development and progression.
subject
GBM
Glioblastoma
Oncogene
tGLI1
Tumor Suppressor
TUSC2
contributor
Lo, Hui-Wen (committee chair)
Debinski, Waldemar (committee member)
Gmeiner, William H (committee member)
Kridel, Steven J (committee member)
date
2019-05-24T08:35:53Z (accessioned)
2020-05-23T08:30:17Z (available)
2019 (issued)
degree
Cancer Biology (discipline)
embargo
2020-05-23 (terms)
identifier
http://hdl.handle.net/10339/93999 (uri)
language
en (iso)
publisher
Wake Forest University
type
Dissertation

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