A comprehensive study of epigenetic alterations in hepatocellular carcinoma identifies potential therapeutic targets

BAYO, JUAN; FIORE, ESTEBAN J.; DOMINGUEZ, LUCIANA M.; REAL, ALEJANDRINA; MALVICINI, MARIANA; RIZZO, MANGLIO; ATORRASAGASTI, CATALINA; GARCÍA, MARIANA G; ARGEMI, JOSEPMARIA; MARTINEZ, ELISABETH D.; MAZZOLINI, GUILLERMO D.

JOURNAL OF HEPATOLOGY

ELSEVIER SCIENCE BV

Lugar: Amsterdam; Año: 2019 vol. 71 p. 78 - 90

0168-8278

BACKGROUND AND AIMS:A causal link has recently been established between epigenetic alterations and hepatocarcinogenesis, indicating that epigenetic inhibition may have therapeutic potential. We aimed to identify and target epigenetic modifiers that show molecular alterations in hepatocellular carcinoma (HCC).METHODS:We studied the molecular-clinical correlations of epigenetic modifiers including bromodomains, histone acetyltransferases, lysine methyltransferases and lysine demethylases in HCC using the Cancer Genome Atlas (TCGA) data of 365 HCC. The therapeutic potential of epigenetic inhibitors was evaluated in vitro and in vivo. RNA-Seq analysis and its correlation with expression and clinical data in the TCGA dataset were used to identify expression programs normalized by Jumonji lysine demethylases (JmjC) inhibitors.RESULTS:Genetic alterations, aberrant expression, and correlation between tumor expression and poor patient prognosis of epigenetic enzymes are common events in HCC. Epigenetic inhibitors that target bromodomain (JQ-1), lysine methyltransferases (BIX-1294 and LLY-507) and JmjC KDMs (JIB-04, GSK-J4 and SD-70) reduce HCC aggressiveness. The pan-JmjC inhibitor JIB-04 had a potent antitumor effect in tumor bearing mice. HCC cells treated with JmjC inhibitors showed overlapping changes in expression programs related with inhibition of cell proliferation and induction of cell death. JmjC inhibition reverts an HCC aggressive gene expression program that is also altered in HCC patients. Several genes downregulated by JmjC inhibitors are highly expressed in tumor vs. non-tumor parenchyma, and their high expression correlates with a poor prognosis. We identified and validated a 4-gene expression prognostic signature consisting of CENPA, KIF20A, PLK1, and NCAPG.CONCLUSIONS:The epigenetic alterations identified in HCC can be used for prognosis prediction and to define a sub-group of high-risk patients that potentially may benefit from JmjC inhibitor therapy.LAY SUMMARY:In this study, we found that mutations and changes in expression of epigenetic modifiers are common events in human HCC, leading to an aggressive gene expression program and poor clinical prognosis. The transcriptional program can be reversed by pharmacological inhibiton of Jumonji enzymes blocking HCC, providing a novel potential therapeutic strategy.