Inhibition of LSD1 sensitizes glioblastoma cells to histone deacetylase inhibitors

Melissa M. Singh, Christa A. Manton, Krishna P. Bhat, Wen Wei Tsai, Kenneth Aldape, Michelle C. Barton, Joya Chandra

Research output: Contribution to journalArticlepeer-review

90 Scopus citations

Abstract

Glioblastoma multiforme (GBM) is a particularly aggressive brain tumor and remains a clinically devastating disease. Despite innovative therapies for the treatment of GBM, there has been no significant increase in patient survival over the past decade. Enzymes that control epigenetic alterations are of considerable interest as targets for cancer therapy because of their critical roles in cellular processes that lead to oncogenesis. Several inhibitors of histone deacetylases (HDAC ss s) have been developed and tested in GBM with moderate success. We found that treatment of GBM cells with HDAC inhibitors caused the accumulation of histone methylation, a modification removed by the lysine specific demethylase 1 (LSD1). This led us to examine the effects of simultaneously inhibiting HDAC s and LSD1 as a potential combination therapy. We evaluated induction of apoptosis in GBM cell lines after combined inhibition of LSD1 and HDAC s. LSD1 was inhibited by targeted short hairpin RNA or pharmacological means and inhibition of HDAC s was achieved by treatment with either vorinostat or PCI-24781. Caspase-dependent apoptosis was significantly increased (>2-fold) in LSD1-knockdown GBM cells treated with HDAC inhibitors. Moreover, pharmacologically inhibiting LSD1 with the monoamine oxidase inhibitor tranylcypromine, in combination with HDAC inhibitors, led to synergistic apoptotic cell death in GBM cells; this did not occur in normal human astrocytes. Taken together, these results indicate that LSD1 and HDAC s cooperate to regulate key pathways of cell death in GBM cell lines but not in normal counterparts, and they validate the combined use of LSD1 and HDAC inhibitors as a therapeutic approach for GBM.

Original languageEnglish (US)
Pages (from-to)894-903
Number of pages10
JournalNeuro-Oncology
Volume13
Issue number8
DOIs
StatePublished - Aug 2011
Externally publishedYes

Keywords

  • Combination therapy
  • Epigenetics
  • Glioblastoma
  • HDAC inhibitors.

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

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