A unique histone deacetylase inhibitor alters microRNA expression and signal transduction in chemoresistant ovarian cancer cells

Curt Balch, Kaleb Naegeli, Seungyoon Nam, Brett Ballard, Alan Hyslop, Christina Melki, Elizabeth Reilly, Man Wook Hur, Kenneth P. Nephew

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Previously, we demonstrated potent antineoplastic activity of a distinctive histone deacetylase inhibitor (HDACI), AR 42, against chemoresistant CP70 ovarian cancer cells in vitro and in vivo. Here, in follow-up to that work, we explored AR 42 global mechanisms-of-action by examining drug-associated, genome-wide microRNA and mRNA expression profiles, which differed from those of the well-studied HDACI vorinostat. Expression of microRNA genes in negative correlation with their "target" coding gene (mRNA) transcripts, and transcription factor genes with expression positively correlated with coding genes having their cognate binding sites were identified and subjected to gene ontology analyses. Those evaluations showed AR 42 gene expression patterns to negatively correlate with Wnt signaling (> 18-fold induction of SFRP1), the epithelial-to-mesenchymal transition (40% decreased ATF1) and cell cycle progression (33-fold increased 14-3-3σ). By contrast, AR 42 transcriptome alterations correlated positively with extrinsic ("death receptor") apoptosis (> 2.3-fold upregulated DAPK) and favorable ovarian cancer histopathology and prognosis. Inhibition of Wnt signaling was experimentally validated by: (1) >2.6-fold reduced Wnt reporter activity, and (2) 36% reduction in nuclear, activated β-catenin. AR 42 induction of multiple (type I or type II autophagic) cell death cascades was further supported by 57% decreased reliance upon reactive oxygen, increased mitochondrial membrane disruption and caspase independence, as compared with vorinostat. Taken together, we demonstrate distinct antineoplastic pathway alterations, in aggressive ovarian cancer cells, following treatment with a promising HDACI, AR 42. These combined computational and experimental approaches may also represent a straightforward means for mechanistic studies of other promising antineoplastics, and/ or the identification of agents that may complement epigenetic therapies.

Original languageEnglish (US)
Pages (from-to)682-694
Number of pages13
JournalCancer Biology and Therapy
Volume13
Issue number8
DOIs
StatePublished - Jun 1 2012

Keywords

  • Epithelial-to-mesenchymal transition
  • Histone deacetylase inhibitor
  • Ovarian cancer
  • Wnt signaling
  • microRNA

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

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