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

Han, Bo; Meng, Xiangqi; Wu, Pengfei; Li, Ziwei; Li, Siyi; Zhang, Yangong; Zha, Caijun; Ye, Qile; Jiang, Chuanlu; Cai, Jinquan; Jiang, Tao

doi:10.7150/thno.41219

Cited by 75 publications

(60 citation statements)

References 52 publications

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“…Interestingly, ATRX depletion in fibroblasts leads to a shift in PRC2 localization and function, with a redistribution to ectopic sites and within coding genes, causing a misdeposition of the H3K27me3 in these sites [ 48 ]. For instance, it was recently showed that ATRX knockout in GBM cells triggers [ 81 ] an impoverishment of H3K27me3 in FADD (Fas-associated death domain) promoter region, suggesting that the ATRX/EZH2 complex promoted trimethylation of histone H3K27 in this region, thus silencing it [ 82 ]. In addition, loss of ATRX in malignant peripheral nerve sheath tumors led to an upregulation of PRC2 gene targets expression, thus giving another prove that ATRX deficiency causes a re-expression of silenced genes controlled by PRC2 [ 48 , 83 ].…”

Section: Atrx Interacts With Daxx In Pml Nuclear Bodies Promoting H33 Depositionmentioning

confidence: 99%

The Multiple Facets of ATRX Protein

Valenzuela

Amato

Sgura

et al. 2021

Cancers

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ATRX gene codifies for a protein member of the SWI-SNF family and was cloned for the first time over 25 years ago as the gene responsible for a rare developmental disorder characterized by α-thalassemia and intellectual disability called Alpha Thalassemia/mental Retardation syndrome X-linked (ATRX) syndrome. Since its discovery as a helicase involved in alpha-globin gene transcriptional regulation, our understanding of the multiple roles played by the ATRX protein increased continuously, leading to the recognition of this multifaceted protein as a central “caretaker” of the human genome involved in cancer suppression. In this review, we report recent advances in the comprehension of the ATRX manifold functions that encompass heterochromatin epigenetic regulation and maintenance, telomere function, replicative stress response, genome stability, and the suppression of endogenous transposable elements and exogenous viral genomes.

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Section: Atrx Interacts With Daxx In Pml Nuclear Bodies Promoting H33 Depositionmentioning

confidence: 99%

The Multiple Facets of ATRX Protein

Valenzuela

Amato

Sgura

et al. 2021

Cancers

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“…EZH2 plays a critical part in the development of glioma ( Han et al, 2020 ). Additionally, it was reported that macrophages are involved in glioma development ( Pang et al, 2018 ).…”

Section: Resultsmentioning

confidence: 99%

EZH2-Inhibited MicroRNA-454-3p Promotes M2 Macrophage Polarization in Glioma

Yang

Zhu

et al. 2020

Front. Cell Dev. Biol.

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Glioma is a primary intracranial tumor with high incidence and mortality. The oncogenic role of EZH2 has been reported in glioma. EZH2 inhibited microRNA-454-3p (miR-454-3p) by binding to its promoter in chondrosarcoma cells. Therefore, our study aimed to identify whether EZH2 regulated M2 macrophage polarization in glioma via miR-454-3p. Clinical samples of different grades of glioma and glioma cells were collected and immunohistochemistry and RT-qPCR demonstrated that EZH2 was highly expressed in glioma tissues. Expression of EZH2 was positively correlated with the degree of M2 macrophage polarization in glioma tissues. EZH2 was silenced by lentivirus in glioma cells, which were subsequently co-cultured with macrophages to evaluate its effect on macrophage polarization. miR-454-3p, a down-regulated miR in glioma, was found to be increased after silencing of EZH2. Furthermore, MethPrimer analysis showed that EZH2 silencing inhibited the DNA methylation level of miR-454-3p. Additionally, MS-PCR, dual-luciferase reporter, RIP and RNA pull down assays revealed that miR-454-3p promoted PTEN expression by inhibiting m6A modification through binding to the enzyme YTHDF2. Either inhibition of miR-454-3p or PTEN resulted in promotion of M2 macrophage polarization. Collectively, histone methyltransferase EZH2 inhibited miR-454-3p through methylation modification and promoted m6A modification of PTEN to induce glioma M2 macrophage polarization.

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“…Moreover, EZH2 is involved in regulating the chemical resistance of various malignant tumors and the stemness of CSCs. It has been shown that EZH2 is upregulated in glioma and glioma CSCs (39)(40)(41). Furthermore, inhibiting both BMI1 and EZH2 enhances the chemotherapy sensitivity of glioma stem cells (42).…”

Section: Discussionmentioning

confidence: 99%

lncRNA TUG1 inhibits the cancer stem cell‑like properties of temozolomide‑resistant glioma cells by interacting with EZH2

et al. 2021

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Temozolomide (TMZ) is currently one of the first-line drugs used for the treatment of high-grade gliomas. However, TMZ resistance results in unsatisfactory therapeutic effects in gliomas. Cancer stem cells (CSCs) have recently been determined to serve a pivotal regulatory role in tumor metastasis, recurrence and chemoresistance. In addition, numerous reports have shown that long non-coding RNAs (lncRNAs) exert an essential role in the occurrence and development of tumors, and can be used as biomarkers for tumor diagnosis and treatment. Among them, studies have revealed that taurine upregulated gene 1 (TUG1) exhibits an important regulatory effect on the malignant biological behavior of glioma cells. Moreover, it has been reported that enhancer of Zeste homolog 2 polycomb repressive complex subunit 2 (EZH2) promotes tumorigenesis, including in glioma. However, the underlying mechanism of the interaction of TUG1 and EZH2 with CSCs of glioma remains elusive, and thus requires further clarification. The present study aimed to explore the role of TUG1 and EZH2 in TMZ resistance in glioma. Cell Counting Kit-8, colony formation,sphere formation and Annexin V-FITC/PI assays were used to detect the proliferation, clone formation efficiency, stemness and apoptosis of TMZ-resistant glioma cells. Xenograft tumor assay was used to detect the effect of TUG1 on the tumorigenesis of TMZ-resistant glioma cells. The present findings demonstrated that TUG1 exhibited a low expression in glioma cells, while EZH2 expression was the opposite. Moreover, it was observed that A172/TMZ cells possessed higher CSCs-like properties compared with parent cells, and that TUG1 and EZH2 were abnormally expressed in A172/TMZ cells. Knockdown of TUG1 or overexpression of EZH2 promoted A172/TMZ cell proliferation and CSCs-like properties, as well as inhibited their apoptosis, thereby enhancing the TMZ resistance of A172/TMZ cells. Furthermore, it was found that TUG1 alleviated the TMZ resistance of A172/TMZ cells by inhibiting EZH2 expression. Of note, overexpression of TUG1 inhibited the tumorigenicity of A172/TMZ cells by downregulating EZH2 expression in vivo.Collectively, the present study demonstrated that TUG1 served an essential regulatory role in TMZ resistance of gliomas.

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

Cited by 75 publications

References 52 publications

The Multiple Facets of ATRX Protein

The Multiple Facets of ATRX Protein

EZH2-Inhibited MicroRNA-454-3p Promotes M2 Macrophage Polarization in Glioma

lncRNA TUG1 inhibits the cancer stem cell‑like properties of temozolomide‑resistant glioma cells by interacting with EZH2

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