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. What's new? The protein KDM1A is strongly expressed in neuroblastomas. Overexpression of this protein correlates with poor patient prognosis, as does reduced expression of the microRNA miR-137. In this study, the authors examined whether miR-137 might act as a tumor suppressor in neuroblastoma, via the down-regulation of KDM1A. Their data led them to conclude that miR-137 does directly target KDM1A mRNA levels in neuroblastoma cells. In addition, increasing the expression of miR-137 resulted in increased apoptosis and decreased cell proliferation of neuroblastoma cells. This may provide a promising therapeutic strategy for aggressive neuroblastomas. Copyright

Additional Metadata
Persistent URL dx.doi.org/10.1002/ijc.28091
Journal International Journal of Cancer
Grant This work was funded by the The Netherlands Organisation for Scientific Research (NWO); grant id nwo/639.072.309 - Statistical Models for Structural Genetic Variants in the Genome of the Netherlands
Citation
Köster, J, Althoff, K. (Kristina), Beckers, A. (Anneleen), Odersky, A. (Andrea), Mestdagh, P. (Pieter), Bray, I.M. (Isabella), … Schulte, J.H. (2013). MiR-137 functions as a tumor suppressor in neuroblastoma by downregulating KDM1A. International Journal of Cancer, 133(5), 1064–1073. doi:10.1002/ijc.28091