title: Integrative genomics identifies YY1AP1 as an oncogenic driver in EpCAM(+) AFP(+) hepatocellular carcinoma.
abstract: Identification of key drivers and new therapeutic targets is important given the poor prognosis for hepatocellular carcinoma (HCC) patients, particularly those ineligible for surgical resection or liver transplant. However, the approach to identify such driver genes is facing significant challenges due to the genomically heterogenous nature of HCC. Here we tested whether the integrative genomic profiling of a well-defined HCC subset that is classified by an extreme EpCAM(+) AFP(+) gene expression signature and associated with poor prognosis, all attributes of a stem cell-like phenotype, could uncover survival-related driver genes in HCC. Following transcriptomic analysis of the well-defined HCC cases, a Gene Set Enrichment Analysis coupled with genomic copy number alteration assessment revealed that YY1-associated protein 1 (YY1AP1) is a critical oncoprotein specifically activated in EpCAM(+) AFP(+) HCC. YY1AP1 silencing eliminates oncogene addiction by altering the chromatin landscape and triggering massive apoptosis in vitro and tumor suppression in vivo. YY1AP1 expression promotes HCC proliferation and is required for the maintenance of stem cell features. We revealed that YY1AP1 cooperates with YY1 to alter the chromatin landscape and activate transcription of stemness regulators. Thus YY1AP1 may serve as a key molecular target for EpCAM(+) AFP(+) HCC subtype. Our results demonstrate the feasibility and power of a new strategy by utilizing well-defined patient samples and integrative genomics to uncover critical pathways linked to HCC subtypes with prognostic impact.
authors.affiliation: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: X
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: S
authors.initials: S
authors.lastname: Parpart
authors.affiliation: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: A
authors.initials: A
authors.lastname: Takai
authors.affiliation: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: S
authors.initials: S
authors.lastname: Roessler
authors.affiliation: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: A
authors.initials: A
authors.lastname: Budhu
authors.affiliation: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: M
authors.initials: M
authors.lastname: Blank
authors.affiliation: Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Y E
authors.initials: YE
authors.lastname: Zhang
authors.affiliation: Liver Cancer Institute, Fudan University, Shanghai, China.
authors.forename: H-L
authors.initials: HL
authors.lastname: Jia
authors.affiliation: Liver Cancer Institute, Fudan University, Shanghai, China.
authors.forename: Q-H
authors.initials: QH
authors.lastname: Ye
authors.affiliation: Liver Cancer Institute, Fudan University, Shanghai, China.
authors.forename: L-X
authors.initials: LX
authors.lastname: Qin
authors.affiliation: Liver Cancer Institute, Fudan University, Shanghai, China.
authors.forename: Z-Y
authors.initials: ZY
authors.lastname: Tang
authors.affiliation: Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: S S
authors.initials: SS
authors.lastname: Thorgeirsson
authors.affiliation: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: X W
authors.initials: XW
authors.lastname: Wang
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002843:Chromatin / Q000378:metabolism; D000071858:Epithelial Cell Adhesion Molecule; D023281:Genomics; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D059467:Transcriptome; D000509:alpha-Fetoproteins / Q000378:metabolism*
chemical_list: D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; D018797:Cell Cycle Proteins; D002843:Chromatin; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; D009687:Nuclear Proteins; D014157:Transcription Factors; C456659:YY1AP1 protein, human; D000509:alpha-Fetoproteins