A comprehensive study of epigenetic alterations in hepatocellular carcinoma identifies potential therapeutic targets
Background & 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 carcino...
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| Tipo de documento: | Artículo |
| Estado: | Published version |
| Fecha de publicación: | 2019 |
| País: | Argentina |
| Institución: | Consejo Nacional de Investigaciones Científicas y Técnicas |
| Repositorio: | CONICET Digital (CONICET) |
| Lenguaje: | Inglés |
| OAI Identifier: | oai:ri.conicet.gov.ar:11336/160865 |
| Acceso en línea: | http://hdl.handle.net/11336/160865 |
| Nivel de acceso: | Acceso abierto |
| Palabra clave: | BROMODOMAINS EPIGENETIC EPIGENETIC INHIBITORS GENE EXPRESSION SIGNATURE HISTONE ACETYLTRANSFERASES HISTONE DEMETHYLASES HISTONE METHYLTRANSFERASES HUMAN HEPATOCELLULAR CARCINOMA JUMONJI C DEMETHYLASES LYSINE DEMETHYLASES PATIENT SURVIVAL https://purl.org/becyt/ford/3.3 https://purl.org/becyt/ford/3 |
| _version_ | 1878403650591653888 |
|---|---|
| author | Bayo Fina, Juan Miguel |
| author2 | Fiore, Esteban Juan Domínguez, Luciana María Real, Alejandrina Malvicini, Mariana Rizzo, Manglio Miguel Atorrasagasti, María Catalina García, Mariana G. Argemi, Josepmaria Martinez, Elisabeth D. Mazzolini Rizzo, Guillermo Daniel |
| author2_role | author author author author author author author author author author |
| author_browse | Argemi, Josepmaria Atorrasagasti, María Catalina Bayo Fina, Juan Miguel Domínguez, Luciana María Fiore, Esteban Juan García, Mariana G. Malvicini, Mariana Martinez, Elisabeth D. Mazzolini Rizzo, Guillermo Daniel Real, Alejandrina Rizzo, Manglio Miguel |
| author_facet | Bayo Fina, Juan Miguel Fiore, Esteban Juan Domínguez, Luciana María Real, Alejandrina Malvicini, Mariana Rizzo, Manglio Miguel Atorrasagasti, María Catalina García, Mariana G. Argemi, Josepmaria Martinez, Elisabeth D. Mazzolini Rizzo, Guillermo Daniel |
| author_role | author |
| collection | CONICET Digital (CONICET) |
| description | Background & 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 patients with HCC. The therapeutic potential of epigenetic inhibitors was evaluated in vitro and in vivo. RNA sequencing analysis and its correlation with expression and clinical data in the TCGA dataset were used to identify expression programs normalized by Jumonji lysine demethylase (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 lysine demethylases (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 reverses an aggressive HCC gene expression program that is also altered in patients with HCC. 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 to predict prognosis and to define a subgroup of high-risk patients that would potentially 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 hepatocellular carcinoma, leading to an aggressive gene expression program and poor clinical prognosis. The transcriptional program can be reversed by pharmacological inhibition of Jumonji enzymes. This inhibition blocks hepatocellular carcinoma progression, providing a novel potential therapeutic strategy. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | AR_a6f26ff8593ea36d6f26cc7166595e4e |
| identifier_str_mv | Bayo Fina, Juan Miguel; Fiore, Esteban Juan; Domínguez, Luciana María; Real, Alejandrina; Malvicini, Mariana; et al.; A comprehensive study of epigenetic alterations in hepatocellular carcinoma identifies potential therapeutic targets; Elsevier Science; Journal of Hepatology; 71; 1; 3-2019; 78-90 0168-8278 CONICET Digital CONICET |
| institution | Consejo Nacional de Investigaciones Científicas y Técnicas |
| instname_str | Consejo Nacional de Investigaciones Científicas y Técnicas |
| language | eng |
| network_acronym_str | AR |
| network_name_str | Argentina |
| oai_identifier_str | oai:ri.conicet.gov.ar:11336/160865 |
| publishDate | 2019 |
| publishDateSort | 2019 |
| publisher | Elsevier Science |
| publisherStr | Elsevier Science |
| reponame_str | CONICET Digital (CONICET) |
| spelling | A comprehensive study of epigenetic alterations in hepatocellular carcinoma identifies potential therapeutic targets Bayo Fina, Juan Miguel Fiore, Esteban Juan Domínguez, Luciana María Real, Alejandrina Malvicini, Mariana Rizzo, Manglio Miguel Atorrasagasti, María Catalina García, Mariana G. Argemi, Josepmaria Martinez, Elisabeth D. Mazzolini Rizzo, Guillermo Daniel BROMODOMAINS EPIGENETIC EPIGENETIC INHIBITORS GENE EXPRESSION SIGNATURE HISTONE ACETYLTRANSFERASES HISTONE DEMETHYLASES HISTONE METHYLTRANSFERASES HUMAN HEPATOCELLULAR CARCINOMA JUMONJI C DEMETHYLASES LYSINE DEMETHYLASES PATIENT SURVIVAL https://purl.org/becyt/ford/3.3 https://purl.org/becyt/ford/3 Background & 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 patients with HCC. The therapeutic potential of epigenetic inhibitors was evaluated in vitro and in vivo. RNA sequencing analysis and its correlation with expression and clinical data in the TCGA dataset were used to identify expression programs normalized by Jumonji lysine demethylase (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 lysine demethylases (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 reverses an aggressive HCC gene expression program that is also altered in patients with HCC. 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 to predict prognosis and to define a subgroup of high-risk patients that would potentially 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 hepatocellular carcinoma, leading to an aggressive gene expression program and poor clinical prognosis. The transcriptional program can be reversed by pharmacological inhibition of Jumonji enzymes. This inhibition blocks hepatocellular carcinoma progression, providing a novel potential therapeutic strategy. Fil: Bayo Fina, Juan Miguel. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina Fil: Fiore, Esteban Juan. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina Fil: Domínguez, Luciana María. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina Fil: Real, Alejandrina. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina Fil: Malvicini, Mariana. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina Fil: Rizzo, Manglio Miguel. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina Fil: Atorrasagasti, María Catalina. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina Fil: García, Mariana G.. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina Fil: Argemi, Josepmaria. University of Pittsburgh; Estados Unidos Fil: Martinez, Elisabeth D.. UT Southwestern Medical Center; Estados Unidos Fil: Mazzolini Rizzo, Guillermo Daniel. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina Elsevier Science http://hdl.handle.net/11336/160865 Bayo Fina, Juan Miguel; Fiore, Esteban Juan; Domínguez, Luciana María; Real, Alejandrina; Malvicini, Mariana; et al.; A comprehensive study of epigenetic alterations in hepatocellular carcinoma identifies potential therapeutic targets; Elsevier Science; Journal of Hepatology; 71; 1; 3-2019; 78-90 0168-8278 CONICET Digital CONICET |
| spellingShingle | A comprehensive study of epigenetic alterations in hepatocellular carcinoma identifies potential therapeutic targets Bayo Fina, Juan Miguel BROMODOMAINS EPIGENETIC EPIGENETIC INHIBITORS GENE EXPRESSION SIGNATURE HISTONE ACETYLTRANSFERASES HISTONE DEMETHYLASES HISTONE METHYLTRANSFERASES HUMAN HEPATOCELLULAR CARCINOMA JUMONJI C DEMETHYLASES LYSINE DEMETHYLASES PATIENT SURVIVAL https://purl.org/becyt/ford/3.3 https://purl.org/becyt/ford/3 |
| status_str | publishedVersion |
| title | A comprehensive study of epigenetic alterations in hepatocellular carcinoma identifies potential therapeutic targets |
| title_full | A comprehensive study of epigenetic alterations in hepatocellular carcinoma identifies potential therapeutic targets |
| title_fullStr | A comprehensive study of epigenetic alterations in hepatocellular carcinoma identifies potential therapeutic targets |
| title_full_unstemmed | A comprehensive study of epigenetic alterations in hepatocellular carcinoma identifies potential therapeutic targets |
| title_short | A comprehensive study of epigenetic alterations in hepatocellular carcinoma identifies potential therapeutic targets |
| title_sort | A comprehensive study of epigenetic alterations in hepatocellular carcinoma identifies potential therapeutic targets |
| topic | BROMODOMAINS EPIGENETIC EPIGENETIC INHIBITORS GENE EXPRESSION SIGNATURE HISTONE ACETYLTRANSFERASES HISTONE DEMETHYLASES HISTONE METHYLTRANSFERASES HUMAN HEPATOCELLULAR CARCINOMA JUMONJI C DEMETHYLASES LYSINE DEMETHYLASES PATIENT SURVIVAL https://purl.org/becyt/ford/3.3 https://purl.org/becyt/ford/3 |
| topic_facet | BROMODOMAINS EPIGENETIC EPIGENETIC INHIBITORS GENE EXPRESSION SIGNATURE HISTONE ACETYLTRANSFERASES HISTONE DEMETHYLASES HISTONE METHYLTRANSFERASES HUMAN HEPATOCELLULAR CARCINOMA JUMONJI C DEMETHYLASES LYSINE DEMETHYLASES PATIENT SURVIVAL https://purl.org/becyt/ford/3.3 https://purl.org/becyt/ford/3 |
| url | http://hdl.handle.net/11336/160865 |