Epigenetic alterations are a hallmark of hepatocellular carcinoma and identify potential therapeutic targets

BAYO JUAN; FIORE ESTEBAN; DOMINGUEZ LUCIANA; REAL A; RIZZO MANGLIO; ONORATO A; RODRIGUEZ MARCELO; ATORRASAGASTI CATALINA; GARCIA MARIANA; MALVICINI MARIANA; MAZZOLINI GUILLERMO

MAR DEL PLATA

Congreso; REUNION CONJUNTA DE SAIC SAI SAFIS 2018; 2018

Hepatocellular carcinoma (HCC) is the second leadingcause of cancer-related death worldwide and has no curativeoptions for advanced disease. Recently, a causallink has been established between deregulation of epigeneticmodifiers (EM) which catalyze post-translationalmodification of histones and the hepatocarcinogenesis.Our aim is to investigate EM alterations in HCC and topreclinically assess the therapeutic potential of their inhibition.To this end, the Cancer Genome Atlas datasetof HCC patients (n=365) was analyzed. We found that75% of patients have at least one EM (n=90) mutated.In addition, 43% of the EM are up-regulated when comparedtumor vs. non-tumoral tissues. Kaplan Meier analysisshowed that high expression of 12 EM correlateswith a poor prognosis in HCC patients. Then, in vitro assaysshowed that epigenetic inhibitors that target bromodomain(JQ-1), methyltransferases (BIX-1294 and LLY-507) and Jumonji (JmjC) demethylases (JIB-04, GSK-J4,SD-70 and ML-324) reduced human HCC cell survival,cell cycle arrest and cell death. Even more, the pan-inhibitorof JmjC JIB-04 showed antitumoral effect in micebearing orthotopic HCC. In addition, we performed RNASeqanalysis of HuH7 cells treated with JIB-04, GSK-J4or SD-70 to identify the mechanisms involved in theirantitumoral effect. We found that JmjC inhibitors inducea similar gene expression program related with cell proliferation,and cell death induction on HuH7 cells. Evenmore, we found that several genes depleted by JmjC inhibitorsare highly expressed in tumor vs non-tumor tissuesand that their high expression correlates with a poorprognosis in HCC patients. Finally, we identified a 5 genesignature (CENPA, KIF20A, PLK1, NCAPG and CTH)that could be used for prognosis prediction and potentiallydefines group of patients that could be benefited bya therapy based on JmjC inhibitors. Our results indicatethat EM are interesting targets for therapeutic strategiesagainst HCC.