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Oncotarget. 2015 Apr 20;6(11):9113-24.

Overexpression of mutant Ptch in rhabdomyosarcomas is associated with promoter hypomethylation and increased Gli1 and H3K4me3 occupancy.

Author information

1
Department of Human Genetics, University Medical Center, Göttingen, Germany.
2
Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, MN, USA.
3
Microarray and Deep-Sequencing Core Facility, University Medical Center, Göttingen, Germany.
4
Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany.

Abstract

Mice with heterozygous loss of the tumor suppressor Patched1 (Ptch) develop rhabdomyosarcoma (RMS)-like tumors. However, Ptch transcripts are consistently overexpressed in these tumors. We have recently shown that the upregulated transcripts are derived from the mutated Ptch allele thus leading to the hypothesis that the wild-type allele is repressed during RMS development. Here we describe epigenetic changes taking place at the Ptch locus during RMS development. We showed a lower degree of DNA-methylation in methylation-sensitive CpG regions of the Ptch promoter in RMS compared to normal muscle from heterozygous Ptch animals. In agreement with these results, treatment of heterozygous Ptch mice with the DNA demethylating agent 5-aza-2-deoxycytidine (5-aza-dC) between embryonic days E9.5-E11.5 significantly accelerated RMS formation. Since Ptch promoter methylation occurs after/around E13.5, the window for RMS initiation during embryogenesis, these results provide additional evidence that Ptch promoter hypomethylation may contribute to RMS formation. We have also demonstrated increased trimethylation of histone H3 lysine 4 (H3K4me3) and preferential binding of Gli1, a known Ptch activator, to the mutant locus in RMS. Together, these findings support an alternative model for RMS formation in heterozygous Ptch mice including loss of methylation and concomitant occupancy by activating histone marks of mutant Ptch.

KEYWORDS:

DNA hypomethylation; Gli1; H3K4me3; Ptch; RMS

PMID:
25823816
PMCID:
PMC4496206
DOI:
10.18632/oncotarget.3272
[Indexed for MEDLINE]
Free PMC Article

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