Preclinical activity of combined HDAC and KDM1A inhibition in glioblastoma

Melissa M. Singh, Blake Johnson, Avinashnarayan Venkatarayan, Elsa R. Flores, Jianping Zhang, Xiaoping Su, Michelle Barton, Frederick Lang, Joya Chandra

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

Background. Glioblastoma (GBM) is the most common and aggressive form of brain cancer. Our previous studies demonstrated that combined inhibition of HDAC and KDM1A increases apoptotic cell death in vitro. However, whether this combination also increases death of the glioma stem cell (GSC) population or has an effect in vivo is yet to be determined. Therefore, we evaluated the translational potential of combined HDAC and KDM1A inhibition on patient-derived GSCs and xenograft GBM mouse models. We also investigated the changes in transcriptional programing induced by the combination in an effort to understand the induced molecular mechanisms of GBM cell death. Methods. Patient-derived GSCs were treated with the combination of vorinostat, a pan-HDAC inhibitor, and tranylcypromine, a KDM1A inhibitor, and viability was measured. To characterize transcriptional profiles associated with cell death, we used RNA-Seq and validated gene changes by RT-qPCR and protein expression via Western blot. Apoptosis was measured using DNA fragmentation assays. Orthotopic xenograft studies were conducted to evaluate the effects of the combination on tumorigenesis and to validate gene changes in vivo. Results. The combination of vorinostat and tranylcypromine reduced GSC viability and displayed efficacy in the U87 xenograft model. Additionally, the combination led to changes in apoptosis-related genes, particularly TP53 and TP73 in vitro and in vivo. Conclusions. These data support targeting HDACs and KDM1A in combination as a strategy for GBM and identifies TP53 and TP73 as being altered in response to treatment.

Original languageEnglish (US)
Pages (from-to)1463-1473
Number of pages11
JournalNeuro-Oncology
Volume17
Issue number11
DOIs
StatePublished - Nov 2015
Externally publishedYes

Keywords

  • HDAC inhibitors
  • KDM1A
  • LSD1
  • epigenetics
  • glioblastoma
  • lysine demethylases
  • orthotopic GBM models
  • tranylcypromine

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

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