Integrative genomics identifies YY1AP1 as an oncogenic driver in EpCAM+ AFP+ hepatocellular carcinoma

X. Zhao, S. Parpart, A. Takai, S. Roessler, A. Budhu, Z. Yu, M. Blank, Y. E. Zhang, H. L. Jia, Q. H. Ye, L. X. Qin, Z. Y. Tang, S. S. Thorgeirsson, X. W. Wang

Research output: Contribution to journalReview articlepeer-review

39 Scopus citations

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.

Original languageEnglish
Pages (from-to)5095-5104
Number of pages10
JournalOncogene
Volume34
Issue number39
DOIs
StatePublished - 24 Sep 2015

Bibliographical note

Publisher Copyright:
© 2015 Macmillan Publishers Limited.

Funding

We thank Dr Curtis Harris for critical reading of the manuscript, Dr Zheng-Gang Liu for advice on apoptosis study, Dominic Esposito at the Advanced Technology Program of SAIC-Frederick, Inc., for the help in designing the Tet-C2 inducible construct and Liver Tissue Cell Distribution System (LTCDS) at the University of Minnesota (Minneapolis, MN, USA) for generous donation of normal liver specimens. We also thank Karen Yarrick for the bibliographic assistance. This work was supported by the Intramural Research Grants of the Center for Cancer Research and the US National Cancer Institute Z01 BC 010313, Z01 BC 010877 and Z01 BC 010876.

FundersFunder number
National Institutes of Health
National Cancer InstituteZ01BC010876, Z01BC010877, Z01BC010313, ZIABC011168

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