The antibiotic clofoctol suppresses glioma stem cell proliferation by activating KLF13

Hu, Yan; Zhang, Meilian; Tian, Ningyu; Li, Dengke; Wu, Fan; Hu, Pei-Shan; Wang, Zhixing; Wang, Liping; Hao, Wei; Kang, Jingting; Yin, Bin; Zheng, Zhi; Jiang, Tao; Yuan, Jing; Qiang, Boqin; Han, Wei; Peng, Xiaozhong

doi:10.1172/jci124979

Cited by 45 publications

(42 citation statements)

References 43 publications

(49 reference statements)

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“…In addition to participating in the initiation and progression of glioma, RBPs may also play an important role in the treatment of glioma. The RNA-binding protein, cold shock domain-containing protein E1 (CSDE1, also known as N-ras upstream gene protein, UNR), could function as a target of the anti-glioma stem cell drug, clofoctol, for tumor growth [25]. However, most of the RBPs that participate in glioma tumorigenesis and progression have remained relatively unexplored.…”

Section: Introductionmentioning

confidence: 99%

Integrated Analysis of RNA-Binding Proteins in Glioma

Wang

Tang

Yuan

et al. 2020

Cancers

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RNA-binding proteins (RBPs) play important roles in many cancer types. However, RBPs have not been thoroughly and systematically studied in gliomas. Global analysis of the functional impact of RBPs will provide a better understanding of gliomagenesis and new insights into glioma therapy. In this study, we integrated a list of the human RBPs from six sources—Gerstberger, SONAR, Gene Ontology project, Poly(A) binding protein, CARIC, and XRNAX—which covered 4127 proteins with RNA-binding activity. The RNA sequencing data were downloaded from The Cancer Genome Atlas (TCGA) (n = 699) and Chinese Glioma Genome Atlas (CGGA) (n = 325 + 693). We examined the differentially expressed genes (DEGs) using the R package DESeq2, and constructed a weighted gene co-expression network analysis (WGCNA) of RBPs. Furthermore, survival analysis was also performed based on the univariate and multivariate Cox proportional hazards regression models. In the WGCNA analysis, we identified a key module involved in the overall survival (OS) of glioblastomas. Survival analysis revealed eight RBPs (PTRF, FNDC3B, SLC25A43, ZC3H12A, LRRFIP1, HSP90B1, HSPA5, and BNC2) are significantly associated with the survival of glioblastoma patients. Another 693 patients within the CGGA database were used to validate the findings. Additionally, 3564 RBPs were classified into canonical and non-canonical RBPs depending on the domains that they contain, and non-canonical RBPs account for the majority (72.95%). The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that some non-canonical RBPs may have functions in glioma. Finally, we found that the knockdown of non-canonical RBPs, PTRF, or FNDC3B can alone significantly inhibit the proliferation of LN229 and U251 cells. Simultaneously, RNA Immunoprecipitation (RIP) analysis indicated that PTRF may regulate cell growth and death- related pathways to maintain tumor cell growth. In conclusion, our findings presented an integrated view to assess the potential death risks of glioblastoma at a molecular level, based on the expression of RBPs. More importantly, we identified non-canonical RNA-binding proteins PTRF and FNDC3B, showing them to be potential prognostic biomarkers for glioblastoma.

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Section: Introductionmentioning

confidence: 99%

Integrated Analysis of RNA-Binding Proteins in Glioma

Wang

Tang

Yuan

et al. 2020

Cancers

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“…There are certain limitations to our study. The TME in GBM is complex due to native extrinsic components as well as tumour intrinsic mechanisms [ 7 , 14 ]. We focused on bone marrow-derived cells (CD45 + cells, mainly including MDSCs and TAMs).…”

Section: Discussionmentioning

confidence: 99%

BATF2 prevents glioblastoma multiforme progression by inhibiting recruitment of myeloid-derived suppressor cells

et al. 2021

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The basic leucine zipper ATF-like transcription factor 2 (BATF2) has been implicated in inflammatory responses and anti-tumour effects. Little, however, is known regarding its extracellular role in maintaining a non-supportive cancer microenvironment. Here, we show that BATF2 inhibits glioma growth and myeloid-derived suppressor cells (MDSCs) recruitment. Interestingly, extracellular vesicles (EVs) from BATF2-overexpressing glioma cell lines (BATF2-EVs) inhibited MDSCs chemotaxis in vitro. Moreover, BATF2 inhibited intracellular SDF-1α and contributes to decreased SDF-1α in EVs. In addition, BATF2 downregulation-induced MDSCs recruitment were reversed by blocking SDF-1α/CXCR4 signalling upon AMD3100 treatment. Specifically, detection of EVs in 24 pairs of gliomas and healthy donors at different stages revealed that the abundance of BATF2-positive EVs in plasma (BATF2+ plEVs) can distinguish stage III–IV glioma from stage I–II glioma and healthy donors. Taken together, our study identified novel regulatory functions of BATF2 in regulating MDSCs recruitment, providing a prognostic value in terms of the number of BATF2+ plEVs in glioma stage.

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“…Zebrafish models also offer advantages in terms of ethical and economic issues for the screening of new treatments. After an initial in vitro selection of drugs from traditional Chinese medicine to treat GBM stem cells, the 13 best candidates were evaluated for toxicity and anti-tumoral efficacy in U87MG-zebrafish models, resulting in the selection of clofoctol as the compound with the best activity ascribed to overexpression of a pro-apoptotic factor (KLF13) [ 179 ].…”

Section: Evaluation Of New Treatments For Gbm Using Zebrafish Modementioning

confidence: 99%

Cellular and Molecular Mechanisms Underlying Glioblastoma and Zebrafish Models for the Discovery of New Treatments

Reimunde

Pensado‐López

Crende

et al. 2021

Cancers

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Glioblastoma (GBM) is the most common of all brain malignant tumors; it displays a median survival of 14.6 months with current complete standard treatment. High heterogeneity, aggressive and invasive behavior, the impossibility of completing tumor resection, limitations for drug administration and therapeutic resistance to current treatments are the main problems presented by this pathology. In recent years, our knowledge of GBM physiopathology has advanced significantly, generating relevant information on the cellular heterogeneity of GBM tumors, including cancer and immune cells such as macrophages/microglia, genetic, epigenetic and metabolic alterations, comprising changes in miRNA expression. In this scenario, the zebrafish has arisen as a promising animal model to progress further due to its unique characteristics, such as transparency, ease of genetic manipulation, ethical and economic advantages and also conservation of the major brain regions and blood–brain–barrier (BBB) which are similar to a human structure. A few papers described in this review, using genetic and xenotransplantation zebrafish models have been used to study GBM as well as to test the anti-tumoral efficacy of new drugs, their ability to interact with target cells, modulate the tumor microenvironment, cross the BBB and/or their toxicity. Prospective studies following these lines of research may lead to a better diagnosis, prognosis and treatment of patients with GBM.

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The antibiotic clofoctol suppresses glioma stem cell proliferation by activating KLF13

Cited by 45 publications

References 43 publications

Integrated Analysis of RNA-Binding Proteins in Glioma

Integrated Analysis of RNA-Binding Proteins in Glioma

BATF2 prevents glioblastoma multiforme progression by inhibiting recruitment of myeloid-derived suppressor cells

Cellular and Molecular Mechanisms Underlying Glioblastoma and Zebrafish Models for the Discovery of New Treatments

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