Elevated CXorf67 Expression in PFA Ependymomas Suppresses DNA Repair and Sensitizes to PARP Inhibitors

Han, Jichang; Meng, Yu; Bai, Yiqin; Yu, Jianzhong; Jin, Fei; Li, Chen; Zeng, Rong; Peng, Jinghong; Li, Ao; Song, Xiaomin; Li, Hao; Wu, Dianqing; Li, Lin

doi:10.1016/j.ccell.2020.10.009

Cited by 25 publications

(16 citation statements)

References 32 publications

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“…To directly test the potential role of GPR17 in glioma development, we generated a stable GPR17 -overexpressing cell line with a common used glioma cell line, U87MG (U87-GPR17) [ 25 – 27 ] (Fig. S2 ).…”

Section: Resultsmentioning

confidence: 99%

G-protein-coupled receptor GPR17 inhibits glioma development by increasing polycomb repressive complex 1-mediated ROS production

Liu

Xing

et al. 2021

Cell Death Dis

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Glioma is the most common primary tumor in the central nervous system. However, the development of glioma and effective therapeutic strategies remain elusive. Here, we identify GPR17 as a potential target to treat glioma. Data mining with human LGG and GBM samples reveals that GPR17 is negatively correlated with glioma development. Overexpressing GPR17 inhibits glioma cell proliferation and induces apoptosis by raising ROS levels. GPR17-overexpressing glioma cells are less tumorigenic in the brain than in control cells. Mechanistically, GPR17 inhibits the transcription of RNF2, a key component in the PRC1 complex, through cAMP/PKA/NF-κB signaling, leading to reduced histone H2A monoubiquitination. ChIP-Seq and RNA-Seq analyses reveal KLF9 as a direct target of RNF2. KLF9 mediates the functions of GPR17 and RNF2 in glioma cells. Furthermore, activation of GPR17 by its agonist inhibits glioma formation. Our findings have thus identified GPR17 as a key regulator of glioma development and a potential therapeutic target for gliomas.

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Section: Resultsmentioning

confidence: 99%

G-protein-coupled receptor GPR17 inhibits glioma development by increasing polycomb repressive complex 1-mediated ROS production

Liu

Xing

et al. 2021

Cell Death Dis

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“…The upregulation of EZHIP could have important implications for therapeutic approaches. As reported by Han et al (2020), EZHIP has a conservative PALB2-binding domain which enables its functioning as a competitive inhibitor of BRCA2. Elevated levels of EZHIP prevent the formation of BRCA1-PALB2-BRCA2 complexes thus inhibiting the homologous recombination-mediated DNA repair pathway.…”

Section: Therapeutic Targeting Of Epnsmentioning

confidence: 90%

“…Indeed, in DMG, disruption of H3K27me3-mediated epigenetic regulation is associated with an extremely aggressive course of the disease, typically presenting with sustained tumor growth and polychemotherapy resistance [ 56 , 57 , 58 ]. Similarly, effective chemotherapy regimens for PF-EPN-A are missing [ 59 ] and therapeutic options for relapses are extremely limited [ 5 , 60 , 61 , 62 , 63 ].…”

Section: Molecular Profiles Of Pf-epnsmentioning

confidence: 99%

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Molecular Stratification of Childhood Ependymomas as a Basis for Personalized Diagnostics and Treatment

Zaytseva

Papusha

Novichkova

et al. 2021

Cancers

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Ependymomas are among the most enigmatic tumors of the central nervous system, posing enormous challenges for pathologists and clinicians. Despite the efforts made, the treatment options are still limited to surgical resection and radiation therapy, while none of conventional chemotherapies is beneficial. While being histologically similar, ependymomas show considerable clinical and molecular diversity. Their histopathological evaluation alone is not sufficient for reliable diagnostics, prognosis, and choice of treatment strategy. The importance of integrated diagnosis for ependymomas is underscored in the recommendations of Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy. These updated recommendations were adopted and implemented by WHO experts. This minireview highlights recent advances in comprehensive molecular-genetic characterization of ependymomas. Strong emphasis is made on the use of molecular approaches for verification and specification of histological diagnoses, as well as identification of prognostic markers for ependymomas in children.

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“…A potentially druggable pathway in PFA EPN is EZHIP, although direct targeting of EZHIP might prove difficult to achieve, because no enzymatic activity has hitherto been identified [ 207 ]. High EZHIP expression sensitizes to PARP inhibitors by inhibiting homologous recombination-mediated DNA repair, especially in combination with radiotherapy, indicating this treatment approach as potentially beneficial in PFA [ 208 ]. A recent publication has shown that PFA tumors and patient-derived cell lines with EZHIP overexpression exhibit enhanced glycolysis and tricarboxylic acid cycle (TCA) metabolism, associated with enrichment of H3K27ac at hexokinase-2 , pyruvate dehydrogenase , and AMPKα-2 [ 209 ].…”

Section: Therapeutic Applicationsmentioning

confidence: 99%

Cell-of-Origin and Genetic, Epigenetic, and Microenvironmental Factors Contribute to the Intra-Tumoral Heterogeneity of Pediatric Intracranial Ependymoma

Servidei

Lucchetti

Navarra

et al. 2021

Cancers

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Intra-tumoral heterogeneity (ITH) is a complex multifaceted phenomenon that posits major challenges for the clinical management of cancer patients. Genetic, epigenetic, and microenvironmental factors are concurrent drivers of diversity among the distinct populations of cancer cells. ITH may also be installed by cancer stem cells (CSCs), that foster unidirectional hierarchy of cellular phenotypes or, alternatively, shift dynamically between distinct cellular states. Ependymoma (EPN), a molecularly heterogeneous group of tumors, shows a specific spatiotemporal distribution that suggests a link between ependymomagenesis and alterations of the biological processes involved in embryonic brain development. In children, EPN most often arises intra-cranially and is associated with an adverse outcome. Emerging evidence shows that EPN displays large intra-patient heterogeneity. In this review, after touching on EPN inter-tumoral heterogeneity, we focus on the sources of ITH in pediatric intra-cranial EPN in the framework of the CSC paradigm. We also examine how single-cell technology has shed new light on the complexity and developmental origins of EPN and the potential impact that this understanding may have on the therapeutic strategies against this deadly pediatric malignancy.

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Elevated CXorf67 Expression in PFA Ependymomas Suppresses DNA Repair and Sensitizes to PARP Inhibitors

Cited by 25 publications

References 32 publications

G-protein-coupled receptor GPR17 inhibits glioma development by increasing polycomb repressive complex 1-mediated ROS production

G-protein-coupled receptor GPR17 inhibits glioma development by increasing polycomb repressive complex 1-mediated ROS production

Molecular Stratification of Childhood Ependymomas as a Basis for Personalized Diagnostics and Treatment

Cell-of-Origin and Genetic, Epigenetic, and Microenvironmental Factors Contribute to the Intra-Tumoral Heterogeneity of Pediatric Intracranial Ependymoma

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