Abstract
Glioblastoma Multiforme (GBM) is a lethal primary brain tumor with poor survival lifespan and dismal outcome. Surgical resection of GBM is greatly limited due to the biological significance of brain, giving rise to tumor relapse in GBM patients. Transactive response DNA binding protein-43 (TDP-43) is a DNA/RNA-binding protein known for causing neurodegenerative diseases through post-translational modification; but little is known about its involvement in cancer development. In this study, we found that nutrient deprivation in GBM cell lines elevated TDP-43 expression by a mechanism of evasion from ubiquitin-dependent proteolytic pathway, and subsequently activated the autophagy process. Exogenous overexpression of TDP-43 consistently activated autophagy and suppressed stress-induced apoptosis. The inhibition of autophagy in TDP-43-overexpressing cells effectively increased the apoptotic population under nutrition shortage. Furthermore, we demonstrated that HDAC6 was involved in the activation of autophagy in TDP-43-overexpressing GBM cell lines. The treatment with SAHA, a universal HDAC inhibitor, significantly reduced TDP-43-mediated anti-apoptotic effect. Additionally, the results of immunohistochemistry showed that TDP-43 and HDAC6 collaborated in GBM-tumor lesions and negatively correlated with the relapse-free survival of GBM patients. Taken together, our results suggest that the TDP-43-HDAC6 signaling axis functions as a stress responsive pathway in GBM tumorigenesis and combats nutrient deprivation stress via activating autophagy, while inhibition of HDAC6 overpowers the pathway and provides a novel therapeutic strategy against GBM.
Highlights
Glioblastoma (GBM), classified as Grade IV brain tumor by World Health Organization (WHO), is the most common and aggressive malignant primary brain tumor [1]
To determine whether Transactive response DNA binding protein-43 (TDP-43) is associated with Glioblastoma Multiforme (GBM) stem cell (GSC) property, the soft agar assay for colony formation and suspended sphere formation assay for self-renewal state were performed to determine the anchorage independent growth ability of U87MG cells
We focused on expression of the nutrient deprivationinduced transactive response (TAR) DNA-binding protein (TDP-43) and its downstream effector histone deacetylase-6 (HDAC6) to dissect their involvements in tumorigenesis of GBM
Summary
Glioblastoma (GBM), classified as Grade IV brain tumor by World Health Organization (WHO), is the most common and aggressive malignant primary brain tumor [1]. GBM is a highly differentiated, vascularized and diffusive tumor which is clinically difficult since surgical resection is the major strategy for the therapy [2]. The diffusive nature of GBM makes the boundary between normal brain tissues and GBM hard to define, resulting in clinical difficulty to remove the tumor. Despite a few reports revealing the relationship between TDP-43 and gliomas, little is known about the role of TDP-43 in tumor malignancy and progression [5, 6]. Recent studies indicated that TDP-43 participates in regulation of glucose and lipid metabolism [7,8,9]. TDP-43 was linked to the metabolic consumption through regulating miR-520associated glycolysis in hepatocellular carcinoma [10]
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