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

TY - JOUR

T1 - Targeting glioma stem-like cell survival and chemoresistance through inhibition of lysine-specific histone demethylase KDM2B

AU - Staberg, Mikkel

AU - Rasmussen, Rikke Darling

AU - Michaelsen, Signe Regner

AU - Pedersen, Henriette

AU - Jensen, Kamilla Ellermann

AU - Villingshøj, Mette

AU - Skjoth-Rasmussen, Jane

AU - Brennum, Jannick

AU - Vitting-Seerup, Kristoffer

AU - Poulsen, Hans Skovgaard

AU - Hamerlik, Petra

PY - 2018/3

Y1 - 2018/3

N2 - 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.

AB - 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.

KW - Antineoplastic Agents/administration & dosage

KW - Apoptosis/drug effects

KW - Astrocytes/metabolism

KW - Brain Neoplasms/drug therapy

KW - Cell Line

KW - DNA Damage/drug effects

KW - Drug Resistance, Neoplasm

KW - Etoposide/administration & dosage

KW - F-Box Proteins/genetics

KW - Glioblastoma/drug therapy

KW - Histones/metabolism

KW - Humans

KW - Jumonji Domain-Containing Histone Demethylases/genetics

KW - Lomustine/administration & dosage

KW - Lysine/metabolism

KW - Neoplastic Stem Cells/metabolism

KW - Primary Cell Culture

U2 - 10.1002/1878-0261.12174

DO - 10.1002/1878-0261.12174

M3 - Journal article

C2 - 29360266

SN - 1574-7891

VL - 12

SP - 406

EP - 420

JO - Molecular Oncology

JF - Molecular Oncology

IS - 3

ER -