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

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.

• Authors: Bo Han, Xiangqi Meng, Pengfei Wu, Ziwei Li, Siyi Li, Yangong Zhang, Caijun Zha, Qile Ye, Chuanlu Jiang, Jinquan Cai, Tao Jiang
• Journal: Theranostics (Theranostics) Vol. 10 Issue 7 Pg. 3351-3365 ( 2020) ISSN: 1838-7640 [Electronic] Australia
• PMID: 32194873 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The author(s).

Chemical References

• Antineoplastic Agents, Alkylating
• DNA, Neoplasm
• DNA-Binding Proteins
• FADD protein, human
• Fas-Associated Death Domain Protein
• Neoplasm Proteins
• Proto-Oncogene Proteins
• STAT5 Transcription Factor
• STAT5B protein, human
• Dioxygenases
• TET2 protein, human
• EZH2 protein, human
• Enhancer of Zeste Homolog 2 Protein
• PARP1 protein, human
• Poly (ADP-Ribose) Polymerase-1
• ATRX protein, human
• X-linked Nuclear Protein
• Temozolomide

Topics

• Animals
• Antineoplastic Agents, Alkylating (pharmacology, therapeutic use)
• Brain Neoplasms (drug therapy, genetics, metabolism)
• CRISPR-Cas Systems
• DNA Damage
• DNA Methylation
• DNA Repair
• DNA, Neoplasm (genetics)
• DNA-Binding Proteins (physiology)
• Dioxygenases
• Drug Resistance, Neoplasm (genetics)
• Enhancer of Zeste Homolog 2 Protein (genetics, physiology)
• Fas-Associated Death Domain Protein (physiology)
• Gene Editing
• Gene Expression Regulation, Neoplastic (genetics)
• Gene Knockout Techniques
• Glioma (drug therapy, genetics, metabolism)
• Histone Code
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasm Proteins (physiology)
• Poly (ADP-Ribose) Polymerase-1 (physiology)
• Promoter Regions, Genetic
• Proto-Oncogene Proteins (physiology)
• STAT5 Transcription Factor (physiology)
• Temozolomide (pharmacology, therapeutic use)
• Tumor Stem Cell Assay
• Up-Regulation
• X-linked Nuclear Protein (antagonists & inhibitors, genetics, physiology)
• Xenograft Model Antitumor Assays