Epigenetic dysregulation of key developmental genes in radiation‐induced rat mammary carcinomas

Abstract

With the increase in the number of long-term cancer survivors worldwide, there is a growing concern about the risk of secondary cancers induced by radiotherapy. Epigenetic modifications of genes associated with carcinogenesis are attractive targets for the prevention of cancer owing to their reversible nature. To identify genes with possible changes in functionally relevant DNA methylation patterns in mammary carcinomas induced by radiation exposure, we performed microarray-based global DNA methylation and expression profiling in γ-ray-induced rat mammary carcinomas and normal mammary glands. The gene expression profiling identified dysregulation of developmentally related genes, including the downstream targets of polycomb repressive complex 2 (PRC2) and overexpression of enhancer of zeste homolog 2, a component of PRC2, in the carcinomas. By integrating expression and DNA methylation profiles, we identified ten hypermethylated and three hypomethylated genes that possibly act as tumor-suppressor genes and oncogenes dysregulated by aberrant DNA methylation; half of these genes encode developmental transcription factors. Bisulfite sequencing and quantitative PCR confirmed the dysregulation of the polycomb-regulated developmentally related transcription-factor genes Dmrt2, Hoxa7, Foxb1, Sox17, Lhx8, Gata3 and Runx1. Silencing of Hoxa7 was further verified by immunohistochemistry. These results suggest that, in radiation-induced mammary gland carcinomas, PRC2-mediated aberrant DNA methylation leads to dysregulation of developmentally related transcription-factor genes. Our findings provide clues to molecular mechanisms linking epigenetic regulation and radiation-induced breast carcinogenesis and underscore the potential of such epigenetic mechanisms as targets for cancer prevention.

Analysis of exosomal circRNAs upon irradiation in pancreatic cancer cell repopulation

“…The red circle indicated the up-regulated circRNAs and the green ones indicated the down-regulated ones which mediated gene transcription [30]. Furthermore, aberrant methylation could lead to dysregulation of related transcription-factor genes, which might be closely bound up to irradiation [31,32]. KEGG analysis indicated that the lysine degradation was important, which was consistent with the results of GO analysis.…”

Neutron-induced Rat Mammary Carcinomas Are Mainly of Luminal Subtype and Have Multiple Copy Number Aberrations

“…Moreover, various animal experiments have revealed that neutrons have a strong effect on mammary carcinogenesis (8). Other studies have revealed various genomic and epigenomic alterations in radiation-induced cancers (9,10). Although copy number aberrations are common in many types of tumors, there are only a few findings on genetic alterations of cancers induced by neutrons (11).…”

Analysis of exosomal circRNAs upon irradiation in pancreatic cancer cell repopulation

“…As reported, VDR and p53 in irradiated HEK 293T was related to various biological effects, which mediated gene transcription [30] . Furthermore, aberrant methylation could lead to dysregulation of related transcription-factor genes, which might be closely bound up to irradiation [31,32] . KEGG analysis indicated that the lysine degradation was important, which was consistent with the results of GO analysis.…”