Retrotransposon-specific DNA hypomethylation and two-step loss-of-imprinting during WW45 haploinsufficiency-induced hepatocarcinogenesis

Abstract: Liver cancer development follows a multistep process that includes epigenetic changes beginning at the initiation stage, changes that have been studied for their potential diagnostic value. Here, we examined long-term, cancer-associated epigenetic changes during carcinogenesis using a mouse model of liver cancer. WW45-haploinsufficient (WW45 +/−) mice developed liver cancer after 12months due to dysregulation of the Hippo pathway and consequent Yap overexpression. There was no pathological sign of neoplastic regions in the livers of 10-month-old WW45 +/− mice but whole-gene expression patterns statistically proved the resemblance between 10-month-old livers and hepatomas from WW45 +/− mice. We found epigenetic features in the livers of 10-month-old WW45 +/− mice which were already distinctive from the wild-type counterparts prior to tumorigenesises. H19 ICR showed loss-of-imprinting in two steps and allelic histone marker signature during tumorigenesis showed similarity with ES cells. Progressive cancer pathognomonic global hypomethylation was a characteristic post-10-month feature and was well reflected in retrotransposons. Heterochromatic histone modifications also decreased in retrotransposons after 10months in the liver of WW45 +/− mice. This study showed potential epigenetic features for cancer prognostic use and supported the epigenetic progenitor model of cancer. [ABSTRACT FROM AUTHOR]