Oligoamine analogues in combination with 2-difluoromethylornithine synergistically induce re-expression of aberrantly silenced tumour-suppressor genes

Yu Wu, Nora Steinbergs, Tracy Murray Stewart, Laurence J. Marton, Robert A Casero

Research output: Contribution to journalArticle

Abstract

Epigenetic gene silencing is an important mechanism in the initiation and progression of cancer. Abnormal DNA CpG island hypermethylation and histone modifications are involved in aberrant silencing of tumour-suppressor genes. LSD1 (lysine-specific demethylase 1) was the first enzyme identified to specifically demethylate H3K4 (Lys 4 of histone H3). Methylated H3K4 is an important mark associated with transcriptional activation. The flavin adenine dinucleotidebinding amine oxidase domain of LSD1 is homologous with two polyamine oxidases, SMO (spermine oxidase) and APAO (N 1- acetylpolyamine oxidase).We have demonstrated previously that long-chain polyamine analogues, the oligoamines, are inhibitors of LSD1. In the present paper we report the synergistic effects of specific oligoamines in combination with DFMO (2-difluoromethylornithine), an inhibitor of ornithine decarboxylase, in human colorectal cancer cells. DFMO treatment depletes natural polyamines and increases the uptake of exogenous polyamines. The combination of oligoamines and DFMO results in a synergistic re-expression of aberrantly silenced tumour-suppressor genes, including SFRP2 (secreted frizzled-related protein 2), which encodes a Wnt signalling pathway antagonist and plays an anti-tumorigenic role in colorectal cancer. The treatment-induced re-expression of SFRP2 is associated with increased H3K4me2 (di-methyl H3K4) in the gene promoter. The combination of LSD1-inhibiting oligoamines and DFMO represents a novel approach to epigenetic therapy of cancer.

Original languageEnglish (US)
Pages (from-to)693-701
Number of pages9
JournalBiochemical Journal
Volume442
Issue number3
DOIs
StatePublished - Mar 15 2012

Fingerprint

Eflornithine
Tumor Suppressor Genes
Lysine
Tumors
Polyamines
Genes
Epigenomics
Histones
Colorectal Neoplasms
Histone Code
CpG Islands
Wnt Signaling Pathway
Population Growth
Gene Silencing
Adenine
Transcriptional Activation
Amines
Neoplasms
Oxidoreductases
Chemical activation

Keywords

  • Epigenetic
  • Histone
  • Lysine-specific demethylase 1 (LSD1)
  • Ornithine decarboxylase
  • Polyamine

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Oligoamine analogues in combination with 2-difluoromethylornithine synergistically induce re-expression of aberrantly silenced tumour-suppressor genes. / Wu, Yu; Steinbergs, Nora; Murray Stewart, Tracy; Marton, Laurence J.; Casero, Robert A.

In: Biochemical Journal, Vol. 442, No. 3, 15.03.2012, p. 693-701.

Research output: Contribution to journalArticle

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