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

Jespersen, Christine and Soragni, Elisabetta and Chou, C. James and Arora, Paramjit S. and Dervan, Peter B. and Gottesfeld, Joel M. (2012) Chromatin structure determines accessibility of a hairpin polyamide–chlorambucil conjugate at histone H4 genes in pancreatic cancer cells. Bioorganic and Medicinal Chemistry Letters, 22 (12). pp. 4068-4071. ISSN 0960-894X. PMCID PMC3362666. https://resolver.caltech.edu/CaltechAUTHORS:20120625-160448430

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1016/j.bmcl.2012.04.090DOIArticle
http://www.sciencedirect.com/science/article/pii/S0960894X12005409PublisherArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3362666/PubMed CentralArticle
ORCID:
AuthorORCID
Dervan, Peter B.0000-0001-8852-7306
Additional Information:© 2012 Elsevier Ltd. Received 29 February 2012; Accepted 16 April 2012; Available online 25 April 2012. This work was supported by a grant from the National Cancer Institute (CA107311) to J.M.G. and P.B.D.
Funders:
Funding AgencyGrant Number
National Cancer InstituteCA107311
Subject Keywords:pyrrole-imidazole polyamide, chlorambucil, gene targeting agent, chromatin immunoprecipitation, MIA PaCa-2 cells
Issue or Number:12
PubMed Central ID:PMC3362666
Record Number:CaltechAUTHORS:20120625-160448430
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20120625-160448430
Official Citation:Christine Jespersen, Elisabetta Soragni, C. James Chou, Paramjit S. Arora, Peter B. Dervan, Joel M. Gottesfeld, Chromatin structure determines accessibility of a hairpin polyamide–chlorambucil conjugate at histone H4 genes in pancreatic cancer cells, Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 12, 15 June 2012, Pages 4068-4071, ISSN 0960-894X, 10.1016/j.bmcl.2012.04.090.
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:32072
Collection:CaltechAUTHORS
Deposited By: Aucoeur Ngo
Deposited On:26 Jun 2012 14:49
Last Modified:26 Nov 2019 11:15

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