TDP-43/HDAC6 axis promoted tumor progression and regulated nutrient deprivation-induced autophagy in glioblastoma

// Tzu-Wei Lin 1 , Ming-Teh Chen 2, 3, 4 , Liang-Ting Lin 8 , Pin-I Huang 3, 6 , Wen-Liang Lo 9 , Yi-Ping Yang 5, 11 , Kai-Hsi Lu 12 , Yi-Wei Chen 3, 6 , Shih-Hwa Chiou 3, 5, 10 and Cheng-Wen Wu 1, 3, 7 1 Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan 2 School of Medicine, National Yang-Ming University, Taipei, Taiwan 3 Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan 4 Department of Neurosurgery, Taipei Veterans General Hospital, Taipei, Taiwan 5 Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan 6 Cancer Center, Taipei Veterans General Hospital, Taipei, Taiwan 7 Institute of Biomedical Science, Academia Sinica, Taipei, Taiwan 8 Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong 9 Division of Oral and Maxillofacial Surgery, Department of Stomatology, Taipei Veterans General Hospital, Taipei, Taiwan 10 Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan 11 Department of Neurological Surgery, Tri-Service General Hospital and National Defense Medical Center, Taipei, Taiwan 12 Department of Medical Research and Education, Cheng-Hsin General Hospital, Taipei, Taiwan Correspondence to: Shih-Hwa Chiou, email: shchiou@vghtpe.gov.tw Cheng-Wen Wu, email: cwwu@ym.edu.tw Keywords: TDP-43, autophagy, glioblastoma, HDAC6, nutrient deprivation Received: October 20, 2016      Accepted: March 30, 2017      Published: May 18, 2017 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.