title: KDM1 is a novel therapeutic target for the treatment of gliomas.
abstract: Glioma development is a multistep process, involving alterations in genetic and epigenetic mechanisms. Understanding the mechanisms and enzymes that promote epigenetic changes in gliomas are urgently needed to identify novel therapeutic targets. We examined the role of histone demethylase KDM1 in glioma progression. KDM1 was overexpressed in gliomas and its expression positively correlated with histological malignancy. Knockdown of KDM1 expression or its pharmacological inhibition using pargyline or NCL-1 significantly reduced the proliferation of glioma cells. Inhibition of KDM1 promoted up regulation of the p53 target genes p21 and PUMA. Patient-derived primary GBM cells expressed high levels of KDM1 and pharmacological inhibition of KDM1 decreased their proliferation. Further, KDM1 inhibition reduced the expression of stemness markers CD133 and nestin in GBM cells. Mouse xenograft assays revealed that inhibition of KDM1 significantly reduced glioma xenograft tumor growth. Inhibition of KDM1 increased levels of H3K4-me2 and H3K9-Ac histone modifications, reduced H3K9-me2 modification and promoted expression of p53 target genes (p21 and PUMA), leading to apoptosis of glioma xenograft tumors. Our results suggest that KDM1 is overexpressed in gliomas and could be a potential therapeutic target for the treatment of gliomas.
authors.affiliation: The Department of Obstetrics and Gynecology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA. Sareddy@uthscsa.edu
authors.forename: Gangadhara R
authors.initials: GR
authors.lastname: Sareddy
authors.forename: Binoj C
authors.initials: BC
authors.lastname: Nair
authors.forename: Samaya K
authors.initials: SK
authors.lastname: Krishnan
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Gonugunta
authors.forename: Quan-guang
authors.initials: QG
authors.lastname: Zhang
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Naoki
authors.initials: N
authors.lastname: Miyata
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Brenner
authors.forename: Darrell W
authors.initials: DW
authors.lastname: Brann
authors.forename: Ratna K
authors.initials: RK
authors.lastname: Vadlamudi
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D003521:Cyclopropanes / Q000494:pharmacology / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D056466:Histone Demethylases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D061986:MCF-7 Cells; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010293:Pargyline / Q000494:pharmacology / Q000627:therapeutic use; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C562353:2-(3-(3-benzamido-4-(benzylamino)-4-oxobutoxy)phenyl)cyclopropylamine; D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D001549:Benzamides; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D003521:Cyclopropanes; D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D010293:Pargyline; D056466:Histone Demethylases; C495195:KDM1A protein, human