Targeting glioma stem-like cell survival and chemoresistance through inhibition of lysine-specific histone demethylase KDM2B.

Autor: Staberg M; Department of Radiation Biology, The Finsen Center, Copenhagen University Hospital, Denmark.; Brain Tumor Biology Group, Danish Cancer Society Research Center, Copenhagen, Denmark., Rasmussen RD; Brain Tumor Biology Group, Danish Cancer Society Research Center, Copenhagen, Denmark., Michaelsen SR; Department of Radiation Biology, The Finsen Center, Copenhagen University Hospital, Denmark.; Brain Tumor Biology Group, Danish Cancer Society Research Center, Copenhagen, Denmark., Pedersen H; Brain Tumor Biology Group, Danish Cancer Society Research Center, Copenhagen, Denmark., Jensen KE; Brain Tumor Biology Group, Danish Cancer Society Research Center, Copenhagen, Denmark., Villingshøj M; Department of Radiation Biology, The Finsen Center, Copenhagen University Hospital, Denmark., Skjoth-Rasmussen J; Department of Neurosurgery, Copenhagen University Hospital, Denmark., Brennum J; Department of Neurosurgery, Copenhagen University Hospital, Denmark., Vitting-Seerup K; Brain Tumor Biology Group, Danish Cancer Society Research Center, Copenhagen, Denmark., Poulsen HS; Department of Radiation Biology, The Finsen Center, Copenhagen University Hospital, Denmark., Hamerlik P; Brain Tumor Biology Group, Danish Cancer Society Research Center, Copenhagen, Denmark.
Jazyk: angličtina
Zdroj: Molecular oncology [Mol Oncol] 2018 Mar; Vol. 12 (3), pp. 406-420. Date of Electronic Publication: 2018 Feb 12.
DOI: 10.1002/1878-0261.12174
Abstrakt: 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.
(© 2018 Danish Cancer Society. Published by FEBS Press and John Wiley & Sons Ltd.)
Databáze: MEDLINE
Externí odkaz: