title: RNA binding protein RBM14 promotes radio-resistance in glioblastoma by regulating DNA repair and cell differentiation.
abstract: Glioblastoma multiforme (GBM) is the most aggressive and lethal type of brain tumor. Standard treatment for GBM patients is surgery followed by radiotherapy and/or chemotherapy, but tumors always recur. Traditional therapies seem to fail because they eliminate only the bulk of the tumors and spare a population of stem-like cells termed tumor-initiating cells. The stem-like state and preferential activation of DNA damage response in the GBM tumor-initiating cells contribute to their radio-resistance and recurrence. The molecular mechanisms underlying this efficient activation of damage response and maintenance of stem-like state remain elusive. Here we show that RBM14 controls DNA repair pathways and also prevents cell differentiation in GBM spheres, causing radio-resistance. Knockdown of RBM14 affects GBM sphere maintenance and sensitizes radio-resistant GBM cells at the cellular level. We demonstrate that RBM14 knockdown blocks GBM regrowth after irradiation in vivo. In addition, RBM14 stimulates DNA repair by controlling the DNA-PK-dependent non-homologous end-joining (NHEJ) pathway. These results reveal unexpected functions of the RNA-binding protein RBM14 in control of DNA repair and maintenance of tumor-initiating cells. Targeting the RBM14-dependent pathway may prevent recurrence of tumors and eradicate the deadly disease completely.
authors.affiliation: Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore MD, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Yuan
authors.forename: Charles G
authors.initials: CG
authors.lastname: Eberhart
authors.forename: Mihoko
authors.initials: M
authors.lastname: Kai
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy; D002453:Cell Cycle; D002454:Cell Differentiation / Q000528:radiation effects*; D049109:Cell Proliferation; D004260:DNA Repair / Q000528:radiation effects*; D005455:Fluorescent Antibody Technique; D005720:Gamma Rays; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology* / Q000528:radiation effects; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D011836:Radiation Tolerance; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C436317:RBM14 protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering