Chromatin structure determines accessibility of a hairpin polyamide-chlorambucil conjugate at histone H4 genes in pancreatic cancer cells

Christine Jespersen, Elisabetta Soragni, C. James Chou, Paramjit S. Arora, Peter B. Dervan, Joel M. Gottesfeld

Research output: Contribution to journalArticle

Abstract

We have shown that a specific pyrrole-imidazole polyamide-DNA alkylator (chlorambucil) conjugate, 1R-Chl, alters the growth characteristics of various cancer cell lines in culture, and causes these cells to arrest in the G2/M stage of the cell cycle, without apparent cytotoxicity. This molecule has also shown efficacy in several mouse xenograft models, preventing tumor growth. Previous microarray studies have suggested that members of the histone H4 gene family, H4c and H4j/k, are the primary targets of this molecule, leading to reduced histone mRNA synthesis and growth arrest in cancer cells. In the present study, we examine the effects of 1R-Chl on transcription of other members of the H4 gene family, with the result that mRNA transcription of most genomic copies of H4 are down-regulated by 1R-Chl in a human pancreatic cancer cell line (MIA PaCa-2), but not in a cell line of non-cancerous origin (HEK293 cells). The basis for this differential effect is likely an open chromatin conformation within the H4 genes in cancer cells. Chromatin immunoprecipitation experiments show increased histone acetylation on the histone H4 genes in cancer cells, compared to HEK293 cells, explaining the differential activity of this molecule in cancer versus non-cancer cells.

Original languageEnglish (US)
Pages (from-to)4068-4071
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume22
Issue number12
DOIs
StatePublished - Jun 15 2012

Keywords

  • Chlorambucil
  • Chromatin immunoprecipitation
  • Gene targeting agent
  • MIA PaCa-2 cells
  • Pyrrole-imidazole polyamide

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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