RNA binding protein RBM14 promotes radio-resistance in glioblastoma by regulating DNA repair and cell differentiation

// Ming Yuan 1 , Charles G. Eberhart 2 and Mihoko Kai 1 1 Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore MD, USA 2 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore MD, USA Correspondence: Mihoko Kai, email: // Keywords : GBM, tumor-initiating cell, DNA repair, stem cell maintenance, radio-therapy Received : March 04, 2014 Accepted : April 25, 2014 Published : April 27, 2014 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.