期刊
MOLECULAR ONCOLOGY
卷 12, 期 3, 页码 406-420出版社
WILEY
DOI: 10.1002/1878-0261.12174
关键词
cancer stem-like cell; chemoresistance; epigenetics; glioblastoma; histone demethylase
类别
资金
- Danish Cancer Society Foundation [R146-A9511/R148-A10151]
- Novo Nordisk Foundation [NNF16OC0023146/NNF17OC0026056]
- Bjarne Saxhoff
- Dansk Kraeftforsknings Fond
- Novo Nordisk Fonden [NNF17OC0026056, NNF16OC0023146] Funding Source: researchfish
- The Danish Cancer Society [R148-A10151, R146-A9511] Funding Source: researchfish
Glioblastoma (GBM) ranks among the most lethal cancers, with current therapies offering only palliation. Inter- and intrapatient heterogeneity is a hallmark of GBM, with epigenetically distinct cancer stem-like cells (CSCs) at the apex. Targeting GSCs remains a challenging task because of their unique biology, resemblance to normal neural stem/progenitor cells, and resistance to standard cytotoxic therapy. Here, we find that the chromatin regulator, JmjC domain histone H3K36me2/me1 demethylase KDM2B, is highly expressed in glioblastoma surgical specimens compared to normal brain. Targeting KDM2B function genetically or pharmacologically impaired the survival of patient-derived primary glioblastoma cells through the induction of DNA damage and apoptosis, sensitizing them to chemotherapy. KDM2B loss decreased the GSC pool, which was potentiated by coadministration of chemotherapy. Collectively, our results demonstrate KDM2B is crucial for glioblastoma maintenance, with inhibition causing loss of GSC survival, genomic stability, and chemoresistance.
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