LAUSR

CAAT enhancer binding protein a (C/EBPa) is a Cwidely expressed basic leucine zipper transcription factor that plays diverse roles including the regulation of differentiation and cell-cycle progression. Studies in C/ EBPa-null mice and zebrafish have shown that it promotes liver development and key metabolic functions while inhibiting hepatocyte proliferation. A large body of work by Timchenko et al has shown that C/EBPa function is critically regulated by its phosphorylation at serine 190 (correlating to S193 in mice), which has effects on gene expression, metabolism, proliferation, and carcinogenesis in the liver. These effects are modulated, at least in part, by differential association of C/EBPa with other regulatory proteins including histone deacetylase 1 (HDAC1). In mice, dephosphorylation of S193 (or a phosphorylation-resistant S193A mutant) is associated with the development of liver cancer in chemical carcinogenesis and genetic models. In this issue of Cellular and Molecular Gastroenterology and Hepatology, Rivas et al examine the potential role of C/ EBPa, HDAC1, and the transcription factor Sp5 in the epigenetic regulation of human hepatoblastoma. This is the most common pediatric liver tumor and is characterized histologically by varying features of dedifferentiation. Although children with localized disease often can be managed with resection, those with metastatic or recurrent disease face a worse prognosis. Notably, relatively few oncogenic mutations have been identified in hepatoblastoma (most commonly affecting the WNT/b-catenin and NFE2L2/NRF2 pathways), suggesting that epigenetic regulation may play an important role in the development, histologic appearance, and aggressiveness of this malignancy. The authors used banked hepatoblastoma tissue obtained immediately after surgery and focused on those expressing high levels of C/EBPa and Sp5. Notably, C/EBPa in these tumorswas highly dephosphorylated at S190, consistentwith their findings in mouse models. They evaluated the expression of protein phosphatase 2A (PP2A), a multiprotein complex that has been shown to dephosphorylate C/EBPa, and found that it overexpressed and was bound to C/EBPa in the tumors. Dephosphorylated C/EBPa and HDAC1 formed complexes in both human hepatoblastoma andmouse tumors from transgenic mice carrying the S193Amutant. In addition, Sp5 expression was increased in human hepatoblastoma and formed complexes with HDAC1. Chromatin immunoprecipitation studies of hepatoblastoma specimens found that binding of C/EBPa and Sp5 to known target genes was associated with increased binding of HDAC1 as well as decreased histone acetylation. In the case of Sp5, they showed thesefindings on the promoter of the p21 cell-cycle inhibitory