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

0168-8278

Background and aims: A causal link has recently been established between epigenetic alterationsand hepatocarcinogenesis, indicating that epigenetic inhibition may have therapeutic potential. Weaimed to identify and target epigenetic modifiers that show molecular alterations in hepatocellularcarcinoma (HCC).Methods: We studied the molecular-clinical correlations of epigenetic modifiers includingbromodomains, histone acetyltransferases, lysine methyltransferases and lysine demethylases inHCC using the Cancer Genome Atlas (TCGA) data of 365 HCC. The therapeutic potential ofepigenetic inhibitors was evaluated in vitro and in vivo. RNA-Seq analysis and its correlation withexpression and clinical data in the TCGA dataset were used to identify expression programsnormalized by Jumonji lysine demethylases (JmjC) inhibitors.Results: Genetic alterations, aberrant expression, and correlation between tumor expression andpoor patient prognosis of epigenetic enzymes are common events in HCC. Epigenetic inhibitorsthat target bromodomain (JQ-1), lysine methyltransferases (BIX-1294 and LLY-507) and JmjCKDMs (JIB-04, GSK-J4 and SD-70) reduce HCC aggressiveness. The pan-JmjC inhibitor JIB-04had a potent antitumor effect in tumor bearing mice. HCC cells treated with JmjC inhibitorsshowed overlapping changes in expression programs related with inhibition of cell proliferationand induction of cell death. JmjC inhibition reverts an HCC aggressive gene expression programthat is also altered in HCC patients. Several genes downregulated by JmjC inhibitors are highlyexpressed in tumor vs. non-tumor parenchyma, and their high expression correlates with a poorprognosis. We identified and validated a 4-gene expression prognostic signature consisting ofCENPA, KIF20A, PLK1, and NCAPG.Page 4 of 42Conclusions: The epigenetic alterations identified in HCC can be used for prognosis predictionand to define a sub-group of high-risk patients that potentially may benefit from JmjC inhibitortherapy