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
2304 - Synthetic peptide of tumor–associated antigen L6 formulated with polymer-based adjuvant enhances anti-tumor effects in mice
Presenter: Shih-jen Liu
Session: Poster Display session 1
Resources:
Abstract
4419 - Improving detection level of somatic mosaicism in neurofibromatosis type 1
Presenter: Kristina Karandasheva
Session: Poster Display session 1
Resources:
Abstract
5283 - Preclinical pharmacokinetic/pharmacodynamic (PK/PD) relationship of ABN401, a highly selective Met inhibitor, in gastric and non-small-cell lung cancer models
Presenter: JooSeok Kim
Session: Poster Display session 1
Resources:
Abstract
5488 - Transcription factors of Snail family in the regulation of resistance of breast cancer cells to hypoxic conditions
Presenter: Alvina Khamidullina
Session: Poster Display session 1
Resources:
Abstract
5417 - Metastasis is impaired by endothelial-specific Dll4 loss-of-function through inhibition of epithelial-to-mesenchymal transition and reduction of cancer stem cells and circulating tumour cells
Presenter: Liliana Mendonça
Session: Poster Display session 1
Resources:
Abstract
5494 - Identification of novel and known FGFR gene fusions in Chinese non-small cell lung cancer
Presenter: Weixin Zhao
Session: Poster Display session 1
Resources:
Abstract
3412 - WNT pathway mutations (APC/CTNNB1) and immune checkpoint inhibitors (ICI) response in metastatic non-small cell lung cancer (NSCLC) patients.
Presenter: Francisco Javier Ros Montana
Session: Poster Display session 1
Resources:
Abstract
1815 - Leukocytosis as a negative prognostic factor in patients with lung cancer: Which subpopulation of leukocytes is responsible?
Presenter: Filip Kohutek
Session: Poster Display session 1
Resources:
Abstract
5022 - Identification of MET gene amplifications using next-generation sequencing in non-small cell lung cancer patients
Presenter: Sergi Clavé
Session: Poster Display session 1
Resources:
Abstract
4925 - Prognostic role of CD73 in metastatic Non Small Cell Lung Cancer according to the presence of driver alterations
Presenter: Giulia Galli
Session: Poster Display session 1
Resources:
Abstract