title: MiR-137 functions as a tumor suppressor in neuroblastoma by downregulating KDM1A.
abstract: Neuroblastoma is the most common extracranial solid tumor of childhood, and accounts for ∼15% of all childhood cancer deaths. The histone demethylase, lysine-specific demethylase 1 (KDM1A, previously known as LSD1), is strongly expressed in neuroblastomas, and overexpression correlates with poor patient prognosis. Inducing differentiation in neuroblastoma cells has previously been shown to down regulate KDM1A, and siRNA-mediated KDM1A knockdown inhibited neuroblastoma cell viability. The microRNA, miR-137, has been reported to be downregulated in several human cancers, and KDM1A mRNA was reported as a putative target of miR-137 in colon cancer. We hypothesized that miR-137 might have a tumor-suppressive role in neuroblastoma mediated via downregulation of KDM1A. Indeed, low levels of miR-137 expression in primary neuroblastomas correlated with poor patient prognosis. Re-expressing miR-137 in neuroblastoma cell lines increased apoptosis and decreased cell viability and proliferation. KDM1A mRNA was repressed by miR-137 in neuroblastoma cells, and was validated as a direct target of miR-137 using reporter assays in SHEP and HEK293 cells. Furthermore, siRNA-mediated KDM1A knockdown phenocopied the miR-137 re-expression phenotype in neuroblastoma cells. We conclude that miR-137 directly targets KDM1A mRNA in neuroblastoma cells, and activates cell properties consistent with tumor suppression. Therapeutic strategies to re-express miR-137 in neuroblastomas could be useful to reduce tumor aggressiveness.
authors: Department of Pediatric Oncology and Hematology, University Children's Hospital Essen, Essen, Germany.
authors: Kristina
authors: K
authors: Althoff
authors: Anneleen
authors: A
authors: Beckers
authors: Andrea
authors: A
authors: Odersky
authors: Pieter
authors: P
authors: Mestdagh
authors: Johannes
authors: J
authors: Köster
authors: Isabella M
authors: IM
authors: Bray
authors: Kenneth
authors: K
authors: Bryan
authors: Jo
authors: J
authors: Vandesompele
authors: Frank
authors: F
authors: Speleman
authors: Raymond L
authors: RL
authors: Stallings
authors: Alexander
authors: A
authors: Schramm
authors: Angelika
authors: A
authors: Eggert
authors: Annika
authors: A
authors: Sprüssel
authors: Johannes H
authors: JH
authors: Schulte
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival; D015536:Down-Regulation; D016147:Genes, Tumor Suppressor; D056466:Histone Demethylases / Q000235:genetics* / Q000502:physiology; D006801:Humans; D035683:MicroRNAs / Q000032:analysis / Q000502:physiology*; D009447:Neuroblastoma / Q000235:genetics*
chemical_list: C545567:MIRN137 microRNA, human; D035683:MicroRNAs; D056466:Histone Demethylases; C495195:KDM1A protein, human
keywords: LSD1; epigenetics; miR-137; neuroblastoma