Abstract
The pediatric liver cancer hepatoblastoma (HBL) has a complex etiology which is not yet determined. In contrast to adult liver cancer hepatocellular carcinoma (HCC), pediatric HBL has a low rate of genetic mutations suggesting that other mechanisms play a critical role in development of this disease. A number of recent reports suggested that epigenetic alterations of gene expression are such mechanisms. The epigenetic regulation does not involve alterations in DNA sequence and includes a) methylation of DNA around promoters of genes; b) opening chromatin structure via modification of histones by chromatin remodeling proteins; c) methylation of mRNAs; and d) micro-RNA-mediated control of gene expression. The Liver Tumor Biology Group from Cincinnati Children’s Hospital has recently published two papers which shed light on the role of chromatin-remodeling proteins in epigenetic regulation of HBL. These papers demonstrate that a Poly (ADP-ribose) Polymerase 1 (PARP1)-dependent activation of oncogene transcription via opening DNA regions that are called Aggressive Liver Cancer Domains (ALCDs) is a key event in HBL pathophysiology. Moreover, these studies revealed that the inhibition of PARP1 in HBL-patient derived xenografts reduces tumor growth. In patients with aggressive HBL, PARP1-ALCDs pathway increases expression of HDAC1, Sp5 and oncogenic form of C/EBPα leading to formation of complexes-repressors and subsequent down-regulation of markers of hepatocytes and repression of tumor suppressor p21. This short communication summarizes the studies of the epigenetic remodeling of DNA in pediatric liver cancer by focusing on these two recent studies and on potential development of a therapy for treatments of children with HBL.