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PMID: 23935509 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Reassembly of nucleosomes at the MLH1 promoter initiates resilencing following decitabine exposure.

PLoS genetics ·Vol. 9 ·No. 7 ·2013-00-00 ·Pages e1003636

Hesson LB, Patil V, Sloane MA, Nunez AC, Liu J, Pimanda JE, Ward RL

Abstract

Hypomethylating agents reactivate tumor suppressor genes that are epigenetically silenced in cancer. Inevitably these genes are resilenced, leading to drug resistance. Using the MLH1 tumor suppressor gene as a model, we showed that decitabine-induced re-expression was dependent upon demethylation and eviction of promoter nucleosomes. Following decitabine withdrawal, MLH1 was rapidly resilenced despite persistent promoter demethylation. Single molecule analysis at multiple time points showed that gene resilencing was initiated by nucleosome reassembly on demethylated DNA and only then was followed by remethylation and stable silencing. Taken together, these data establish the importance of nucleosome positioning in mediating resilencing of drug-induced gene reactivation and suggest a role for therapeutic targeting of nucleosome assembly as a mechanism to overcome drug resistance.

MeSH Terms
Adaptor Proteins, Signal Transducing/genetics Azacitidine/administration & dosage,analogs & derivatives Cell Line, Tumor Chromatin Assembly and Disassembly/genetics CpG Islands/genetics DNA Methylation/drug effects,genetics Decitabine Drug Resistance, Neoplasm/drug effects,genetics Gene Expression Regulation, Neoplastic/drug effects Gene Silencing Humans MutL Protein Homolog 1 Nuclear Proteins/genetics Nucleosomes/genetics,metabolism Promoter Regions, Genetic/drug effects
Chemicals
Adaptor Proteins, Signal Transducing MLH1 protein, human Nuclear Proteins Nucleosomes Decitabine MutL Protein Homolog 1 Azacitidine
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Hesson Luke B
Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales, Australia. [email protected]
Patil Vibha
Sloane Mathew A
Nunez Andrea C
Liu Jia
Pimanda John E
Ward Robyn L
Conflict of Interest

The authors have declared that no competing interests exist.

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Article Info
Journal
PLoS genetics
Abbr.
PLoS Genet
ISSN
1553-7404
DOI
10.1371/journal.pgen.1003636
Email
[email protected]
Published
2013-00-00
Epub
2013-00-25
Pages
e1003636
Language
English
Region
United States
NLM ID
101239074
PMCID
PMC3723495
Subset
IM
External Links
PubMed source DOI: 10.1371/journal.pgen.1003636 PMC Full Text View journal details
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