Oncotarget

Research Papers:

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

Tzu-Wei Lin, Ming-Teh Chen, Liang-Tin Lin, Pin-I Huang, Wen-Liang Lo, Yi-Ping Yang, Kai-Hsi Lu, Yi-Wei Chen, Shih-Hwa Chiou and Cheng-Wen Wu _

PDF  |  HTML  |  How to cite

Oncotarget. 2017; 8:56612-56625. https://doi.org/10.18632/oncotarget.17979

Metrics: PDF 2473 views  |   HTML 3977 views  |   ?  


Abstract

Tzu-Wei Lin1, Ming-Teh Chen2,3,4, Liang-Ting Lin8, Pin-I Huang3,6, Wen-Liang Lo9, Yi-Ping Yang5,11, Kai-Hsi Lu12, Yi-Wei Chen3,6, Shih-Hwa Chiou3,5,10 and Cheng-Wen Wu1,3,7

1Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan

2School of Medicine, National Yang-Ming University, Taipei, Taiwan

3Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan

4Department of Neurosurgery, Taipei Veterans General Hospital, Taipei, Taiwan

5Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan

6Cancer Center, Taipei Veterans General Hospital, Taipei, Taiwan

7Institute of Biomedical Science, Academia Sinica, Taipei, Taiwan

8Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong

9Division of Oral and Maxillofacial Surgery, Department of Stomatology, Taipei Veterans General Hospital, Taipei, Taiwan

10Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan

11Department of Neurological Surgery, Tri-Service General Hospital and National Defense Medical Center, Taipei, Taiwan

12Department of Medical Research and Education, Cheng-Hsin General Hospital, Taipei, Taiwan

Correspondence to:

Shih-Hwa Chiou, email: [email protected]

Cheng-Wen Wu, email: [email protected]

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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.
PII: 17979