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

Autor: Petra Hamerlik, Kristoffer Vitting-Seerup, Signe Regner Michaelsen, Jannick Brennum, Jane Skjøth-Rasmussen, Mikkel Staberg, Mette Villingshøj, Henriette Pedersen, Hans Skovgaard Poulsen, Kamilla E. Jensen, Rikke Darling Rasmussen
Rok vydání: 2018
Předmět:
0301 basic medicine
Jumonji Domain-Containing Histone Demethylases
Cancer Research
Histones/metabolism
Apoptosis
Lomustine/administration & dosage
KDM2B
Astrocytes/metabolism
Histones
Jumonji Domain-Containing Histone Demethylases/genetics
Lomustine
Research Articles
Etoposide
biology
Brain Neoplasms
chemoresistance
General Medicine
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Glioblastoma/drug therapy
Antineoplastic Agents/administration & dosage
Chromatin
Histone
Oncology
Neoplastic Stem Cells
F-Box Proteins/genetics
Molecular Medicine
Research Article
Lysine/metabolism
Primary Cell Culture
Etoposide/administration & dosage
Antineoplastic Agents
Brain Neoplasms/drug therapy
lcsh:RC254-282
Cell Line
03 medical and health sciences
Neoplastic Stem Cells/metabolism
histone demethylase
Glioma
Genetics
medicine
Humans
Epigenetics
Progenitor cell
epigenetics
F-Box Proteins
Lysine
Apoptosis/drug effects
glioblastoma
Cancer
cancer stem‐like cell
medicine.disease
030104 developmental biology
Drug Resistance
Neoplasm
Astrocytes
DNA Damage/drug effects
biology.protein
Cancer research
Demethylase
DNA Damage
Zdroj: Staberg, M, Rasmussen, R D, Michaelsen, S R, Pedersen, H, Jensen, K E, Villingshøj, M, Skjoth-Rasmussen, J, Brennum, J, Vitting-Seerup, K, Poulsen, H S & Hamerlik, P 2018, ' Targeting glioma stem-like cell survival and chemoresistance through inhibition of lysine-specific histone demethylase KDM2B ', Molecular Oncology, vol. 12, no. 3, pp. 406-420 . https://doi.org/10.1002/1878-0261.12174
Molecular Oncology
Molecular Oncology, Vol 12, Iss 3, Pp 406-420 (2018)
ISSN: 1574-7891
Popis: 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.
Databáze: OpenAIRE
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