Loss of ATRX suppresses ATM dependent DNA damage repair by modulating H3K9me3 to enhance temozolomide sensitivity in glioma

Han, Bo; Cai, Jinquan; Gao, Weida; Meng, Xiangqi; Gao, Fei; Wu, Pengfei; Duan, Chunbin; Wang, Ruijia; Dinislam, Magafurov; Lin, Lin; Kang, Chunsheng

doi:10.1016/j.canlet.2018.01.056

Cited by 57 publications

(41 citation statements)

References 29 publications

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“…Although the role of IFI30 in glioma malignant progression has been reported, 37 its effect on gliomas of chemotherapy sensitivity is less known. We conducted somatic mutation profiles in GBM patients stratified by IFI30 expression, the results exhibited that IDH1 and ATRX mutated more frequently in low IFI30 group, increasing evidences indicated that IDH1 and ATRX wild type conferred a higher incidence of TMZ resistance, 38,39 which may indicate that IFI30 also has the ability in TMZ sensitivity regulation. By performing analyses in CGGA and TCGA cohorts, we found that high IFI30 expression indeed conferred chemotherapy resistance in GBM.…”

Section: Discussionmentioning

confidence: 99%

<p>IFI30 Is a Novel Immune-Related Target with Predicting Value of Prognosis and Treatment Response in Glioblastoma</p>

Zhu

Chen

Guan

et al. 2020

OTT

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As a crucial part of anti-tumor immunotherapy, interferon-α/β (IFN-α/β) treatment has been broadly applied to clinical trials of glioma. However, less is known about implement of interferon-γ (IFN-γ) in glioma. Further investigating the valuable hub molecular of IFN-γ family might provide us a novel guidance for glioma therapy. Methods: This study carried out an analysis on glioma patients from the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA) cohorts. The analyses were performed by GraphPad Prism 8 and R language. All the validated experiments were performed three times independently. Results: We identified IFI30 as the most stable independent prognostic gene among 20 classical IFN-γ stimulated genes (ISGs) in glioma patients. Furthermore, we found that IFI30 highly expressed in malignant subtypes of glioma and associated with chemotherapy response. We also found IFI30 could activate IL6-STAT6 signal pathway to decline the glioma cells' chemotherapy sensitivity by performing experiments. Gene ontology (GO) analysis showed IFI30 associated with enhanced leucocyte mediated immune and inflammatory response. Microenvironment analysis referred that high IFI30 expression accompanied with more infiltration of M2 type macrophages. Conclusion: IFI30 is involved in the malignant progression and chemotherapy response of glioblastoma, which can be a potential target for treatment in glioblastoma patients.

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Section: Discussionmentioning

confidence: 99%

<p>IFI30 Is a Novel Immune-Related Target with Predicting Value of Prognosis and Treatment Response in Glioblastoma</p>

Zhu

Chen

Guan

et al. 2020

OTT

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“… 135 , 136) Knockdown of ATRX indicates suppression of ATM (ataxia telangiectasia, mutated) dependent DNA damage repair by modulating histone H3 lysine 9 trimethylation (H3K9me3) to enhance TMZ. 137) Nuclear factor erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor reported to regulate the expression of various cytoprotective genes. 138 , 139) Constitutive Nrf2 activation in many cancers enhances cell survival and resistance to anti-cancer drugs, 140 , 141) including TMZ, 142) through glutathione (GSH) synthesis, which plays a critical role in neutralizing reactive oxygen species (ROS) induced by chemotherapy.…”

Section: Strategy For Enhancing Tmz Effectmentioning

confidence: 99%

Potential Strategies Overcoming the Temozolomide Resistance for Glioblastoma

Jiapaer

Furuta

Tanaka

et al. 2018

Neurol. Med. Chir.(Tokyo)

273

211

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Glioblastoma (GBM) is a highly malignant type of primary brain tumor with a high mortality rate. Although the current standard therapy consists of surgery followed by radiation and temozolomide (TMZ), chemotherapy can extend patient’s post-operative survival but most cases eventually demonstrate resistance to TMZ. O6-methylguanine-DNA methyltransferase (MGMT) repairs the main cytotoxic lesion, as O6-methylguanine, generated by TMZ, can be the main mechanism of the drug resistance. In addition, mismatch repair and BER also contribute to TMZ resistance. TMZ treatment can induce self-protective autophagy, a mechanism by which tumor cells resist TMZ treatment. Emerging evidence also demonstrated that a small population of cells expressing stem cell markers, also identified as GBM stem cells (GSCs), contributes to drug resistance and tumor recurrence owing to their ability for self-renewal and invasion into neighboring tissue. Some molecules maintain stem cell properties. Other molecules or signaling pathways regulate stemness and influence MGMT activity, making these GCSs attractive therapeutic targets. Treatments targeting these molecules and pathways result in suppression of GSCs stemness and, in highly resistant cases, a decrease in MGMT activity. Recently, some novel therapeutic strategies, targeted molecules, immunotherapies, and microRNAs have provided new potential treatments for highly resistant GBM cases. In this review, we summarize the current knowledge of different resistance mechanisms, novel strategies for enhancing the effect of TMZ, and emerging therapeutic approaches to eliminate GSCs, all with the aim to produce a successful GBM treatment and discuss future directions for basic and clinical research to achieve this end.

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“…ChIP experiments were performed using the Chromatin Immunoprecipitation (ChIP) Assay Kit (Millipore, 17-295) and conducted following a protocol previously described (19). Briefly, Supplementary Table S5.…”

Section: Chromatin Immunoprecipitation (Chip)mentioning

confidence: 99%

Tumor Cell–Derived TGFβ1 Attenuates Antitumor Immune Activity of T Cells via Regulation of PD-1 mRNA

Geng

Chen

et al. 2020

Cancer Immunology Research

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Dysfunction in T-cell antitumor activity contributes to the tumorigenesis, progression, and poor outcome of clear cell renal cell carcinoma (ccRCC), with this dysfunction resulting from high expression of programmed cell death-1 (PD-1) in T cells. However, the molecular mechanisms maintaining high PD-1 expression in T cells have not been fully investigated in ccRCC. Here, we describe a mechanism underlying the regulation of PD-1 at the mRNA level and demonstrated its impact on T-cell dysfunction. Transcriptomic analysis identified a correlation between transforming growth factor beta 1 (TGFB1) and PDCD1 in ccRCC samples. The mechanism underlying the regulation of PD-1 mRNA was then investigated in vitro and in vivo using syngeneic tumor models. We also observed that TGFβ1 had prognostic significance in ccRCC patients, and its expression was associated with PD-1 mRNA expression. CcRCC-derived TGFβ1 activated P38 and induced the phosphorylation of Ser 10 on H3, which recruited p65 to increase SRSF3 and SRSF5 expression in T cells. As a result, the half-life of PD-1 mRNA in T cells was prolonged. SRSF3 coordinated with NXF1 to induce PD-1 mRNA extranuclear transport in T cells. We then demonstrated that TGFβ1 could induce SRSF3 expression to restrict the antitumor activity of T cells, which influenced immunotherapy outcomes in ccRCC mouse models. Our findings highlight that tumor-derived TGFβ1 mediates immune evasion and has potential as a prognostic biomarker and therapeutic target in ccRCC.

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Loss of ATRX suppresses ATM dependent DNA damage repair by modulating H3K9me3 to enhance temozolomide sensitivity in glioma

Cited by 57 publications

References 29 publications

<p>IFI30 Is a Novel Immune-Related Target with Predicting Value of Prognosis and Treatment Response in Glioblastoma</p>

<p>IFI30 Is a Novel Immune-Related Target with Predicting Value of Prognosis and Treatment Response in Glioblastoma</p>

Potential Strategies Overcoming the Temozolomide Resistance for Glioblastoma

Tumor Cell–Derived TGFβ1 Attenuates Antitumor Immune Activity of T Cells via Regulation of PD-1 mRNA

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