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Theranostics 2020; 10(7):3351-3365. doi:10.7150/thno.41219 This issue Cite

Research Paper

ATRX/EZH2 complex epigenetically regulates FADD/PARP1 axis, contributing to TMZ resistance in glioma

Bo Han^1,2,3, Xiangqi Meng^2✉, Pengfei Wu², Ziwei Li², Siyi Li⁴, Yangong Zhang², Caijun Zha⁵, Qile Ye², Chuanlu Jiang², Jinquan Cai^2✉, Tao Jiang^1,3✉

1. Beijing Neurosurgical Institute, Capital Medical University, Beijing 100050, China
2. Department of Neurosurgery, the Second Affiliated Hospital of Harbin Medical University, Neuroscience Institute, Heilongjiang Academy of Medical Sciences, Harbin 150086, China
3. Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China
4. Department of Mining and Materials Engineering, McGill University, Montreal, QC H2X1X8, Canada
5. Department of Laboratory Diagnosis, the Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China.

✉ Corresponding authors: Jinquan Cai (e-mail: caijinquan666777com). Xiangqi Meng (e-mail: neptune_mxqcom). Tao Jiang (e-mail: taojiang1964com)

Abstract

Rationale: Glioma is the most common primary malignant brain tumor in adults. Chemoresistance of temozolomide (TMZ), the first-line chemotherapeutic agent, is a major issue in the management of patients with glioma. Alterations of alpha thalassemia/mental retardation syndrome X-linked (ATRX) gene constitute one of the most prevalent genetic abnormalities in gliomas. Therefore, elucidation of the role of ATRX contributing to TMZ resistance in glioma is urgently needed.

Methods: We performed the bioinformatics analysis of gene expression, and DNA methylation profiling, as well as RNA and ChIP-seq data sets. CRISPR-Cas9 gene editing system was used to achieve the ATRX knockout in TMZ resistant cells. In vitro and in vivo experiments were carried out to investigate the role of ATRX contributing to TMZ resistance in glioma.

Results: We found that ATRX expression was upregulated via DNA demethylation mediated by STAT5b/TET2 complex and strengthened DNA damage repair by stabilizing PARP1 protein in TMZ resistant cells. ATRX elicited PARP1 stabilization by the down-regulating of FADD expression via the H3K27me3 enrichment, which was dependent on ATRX/EZH2 complex in TMZ resistant cells. Magnetic resonance imaging (MRI) revealed that the PARP inhibitor together with TMZ inhibited glioma growth in ATRX wild type TMZ resistant intracranial xenograft models.

Conclusions: The present study further illustrated the novel mechanism of the ATRX/PARP1 axis contributing to TMZ resistance. Our results provided substantial new evidence that PARP inhibitor might be a potential adjuvant agent in overcoming ATRX mediated TMZ resistance in glioma.

Keywords: glioma, ATRX, TMZ resistance, PARP1, EZH2

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