Abstract 4955
Background
XIAP-associated factor 1 (XAF1) is a pro-apoptotic tumor suppressor whose expression is inactivated in many human malignancies. To explore the XAF1’s candidacy for a suppressor in the pathogenesis of human glioma, we investigated its expression and function in tumor cell lines and tissues.
Methods
Expression study was performed using quantitative RT-PCR and immunoblot assays. Functional interplay between XAF1 and AMPK was determined by gene transfection, siRNA-mediated depletion.
Results
XIAP-associated factor 1 (XAF1) is a pro-apoptotic tumor suppressor whose expression is inactivated in many human malignancies. In this study, we explored the XAF1’s candidacy for a suppressor in human glioma pathogenesis. XAF1 reduction is more common in high grade tumors versus low grade tumors and tightly associated with aberrant hypermethylation at 7 CpG sites in the 5’ proximal region of the promoter. XAF1 expression decreases proliferation and colony-forming ability of glioma cells while its depletion enhances cellular resistance to genotoxic drugs, such as temozolomide (TMZ), etoposide and cisplatin. The XAF1 promoter is activated in response to TMZ through JNK-IRF-1 signaling and its activation greatly increases cellular response to TMZ-induced cell death. Furthermore, XAF1 promotes autophagic cell death (ACD) by activating AMP-activated protein kinase (AMPK) in a XIAP-independent manner. Both AMPK-activating and ACD-inducing effects of XAF1 are linked to its activity to decrease intracellular ATP level, oxygen consumption, and mitochondrial membrane potential. XAF1 proteins translocate to the mitochondria and the zinc finger (ZF) 6 domain is essential for its mitochondrial distribution. Consistently, a mutant XAF1 lacking the ZF6 fails to decrease ATP level, activate AMPK, and trigger AMPK-mediated autophagic cell death. Collectively, this study demonstrates that epigenetic inactivation of XAF1 contributes to the malignant progression of human glioma by rendering tumor cells a survival advantage via the attenuation of AMPK signaling.
Conclusions
Epigenetic inactivation of XAF1 contributes to the malignant progression of human glioma by rendering tumor cells a survival advantage via the attenuation of AMPK signaling.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (No. 2018R1D1A1B07041512).
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
2045 - The analysis of treatment sequences and clinical outcomes of thymic carcinoma
Presenter: Arakaki Motoko
Session: Poster Display session 1
Resources:
Abstract
4785 - Transcriptomic Difference of Thymoma and Thymic Carcinoma
Presenter: Naixin Liang
Session: Poster Display session 1
Resources:
Abstract
2864 - A Phase II Trial of Preoperative Chemoradiotherapy and Pembrolizumab for Locally Advanced Esophageal Squamous Cell Carcinoma (ESCC)
Presenter: Seoyoung Lee
Session: Poster Display session 1
Resources:
Abstract
5015 - The study of tumor associated exosomes in crosstalk between esophageal carcinoma and lymphatic endothelial cells
Presenter: Weimin Mao
Session: Poster Display session 1
Resources:
Abstract
1339 - Up-regulation of IBSP expression predicts poor prognosis of Esophageal Squamous Cell Carcinoma patients
Presenter: Mingyue Wang
Session: Poster Display session 1
Resources:
Abstract
4083 - PD-L1 expression in primary tumour vs metastatic samples in the Phase 3 MYSTIC study in first-line metastatic (m) NSCLC
Presenter: Niels Reinmuth
Session: Poster Display session 1
Resources:
Abstract
5113 - Assessing the impact of subsequent checkpoint inhibitor (CPI) treatment on overall survival: post hoc analyses from the phase 3 JAVELIN Lung 200 study of avelumab vs docetaxel in platinum-treated locally advanced/metastatic non-small cell lung cancer (NSCLC)
Presenter: Fabrice Barlesi
Session: Poster Display session 1
Resources:
Abstract
4256 - Long-term avelumab treatment in patients with advanced non-small cell lung cancer (NSCLC): post hoc analyses from JAVELIN Solid Tumor
Presenter: Borys Hrinczenko
Session: Poster Display session 1
Resources:
Abstract
4305 - Effectiveness and safety of nivolumab in the treatment of lung cancer patients in France: Updated survival and subgroup analysis from the real-world EVIDENS study
Presenter: Fabrice Barlesi
Session: Poster Display session 1
Resources:
Abstract
5128 - IO-Synthesise NSCLC: A pooled analysis of real-world survival outcomes for non-small cell lung cancer patients treated with nivolumab in France and Germany
Presenter: Adrien Dixmier
Session: Poster Display session 1
Resources:
Abstract