Lysine-specific histone demethylase 1A (KDM1A/LSD1) inhibition attenuates DNA double-strand break repair and augments the efficacy of temozolomide in glioblastoma

作者：Salvador Alejo, Bridgitte E. Palacios, Prabhakar Pitta Venkata, Yi He, Wenjing Li, Jessica D. Johnson, Yihong Chen, Sridharan Jayamohan, Uday P. Pratap, K. Clarke, Yi Zou, Yingli Lv, Korri Weldon, Suryavathi Viswanadhapalli, Zhao Lai, Zhenqing Ye, Yidong Chen, Andrea Gilbert, Takayoshi Suzuki, Rajeshwar R. Tekmal, Weixing Zhao, Siyuan Zheng, Ratna K. Vadlamudi, Andrew Brenner, Gangadhara R. Sareddy · 发表于：Neuro-Oncology · 年份：2023 · DOI：10.1093/neuonc/noad018 · 被引用次数：51 · 研究领域：Epigenetics and DNA Methylation、DNA Repair Mechanisms、Glioma Diagnosis and Treatment

BACKGROUND: Efficient DNA repair in response to standard chemo and radiation therapies often contributes to glioblastoma (GBM) therapy resistance. Understanding the mechanisms of therapy resistance and identifying the drugs that enhance the therapeutic efficacy of standard therapies may extend the survival of GBM patients. In this study, we investigated the role of KDM1A/LSD1 in DNA double-strand break (DSB) repair and a combination of KDM1A inhibitor and temozolomide (TMZ) in vitro and in vivo using patient-derived glioma stem cells (GSCs). METHODS: Brain bioavailability of the KDM1A inhibitor (NCD38) was established using LS-MS/MS. The effect of a combination of KDM1A knockdown or inhibition with TMZ was studied using cell viability and self-renewal assays. Mechanistic studies were conducted using CUT&Tag-seq, RNA-seq, RT-qPCR, western blot, homologous recombination (HR) and non-homologous end joining (NHEJ) reporter, immunofluorescence, and comet assays. Orthotopic murine models were used to study efficacy in vivo. RESULTS: TCGA analysis showed KDM1A is highly expressed in TMZ-treated GBM patients. Knockdown or knockout or inhibition of KDM1A enhanced TMZ efficacy in reducing the viability and self-renewal of GSCs. Pharmacokinetic studies established that NCD38 readily crosses the blood-brain barrier. CUT&Tag-seq studies showed that KDM1A is enriched at the promoters of DNA repair genes and RNA-seq studies confirmed that KDM1A inhibition reduced their expression. Knockdown...