Nasopharyngeal carcinoma super-enhancer–driven ETV6 correlates with prognosis

Liangru Ke, Hufeng Zhou, Chong Wang, Geng Xiong, Yanqun Xiang, Yihong Ling, Abdelmajid Khabir, George S. Tsao, Yixin Zeng, Musheng Zeng, Pierre Busson, Elliott Kieff, Xiang Guo, Bo Zhao

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

Abstract

Nasopharyngeal carcinoma (NPC) most frequently occurs in southern China and southeast Asia. Epidemiology studies link NPC to genetic predisposition, Epstein–Barr virus (EBV) infection, and environmental factors. Genetic studies indicate that mutations in chromatin-modifying enzymes are the most frequent genetic alterations in NPC. Here, we used H3K27ac chromatin immune precipitation followed by deep sequencing (ChIP-seq) to define the NPC epigenome in primary NPC biopsies, NPC xenografts, and an NPC cell line, and compared them to immortalized normal nasopharyngeal or oral epithelial cells. We identified NPC-specific enhancers and found these enhancers were enriched with nuclear factor κB (NF-κB), IFN-responsive factor 1 (IRF1) and IRF2, and ETS family members ETS1 motifs. Normal cell-specific enhancers were enriched with basic leucine zipper family members and TP53 motifs. NPC super-enhancers with extraordinarily broad and high H3K27ac signals were also identified, and they were linked to genes important for oncogenesis including ETV6. ETV6 was also highly expressed in NPC biopsies by immunohistochemistry. High ETV6 expression correlated with a poor prognosis. Furthermore, we defined the EBV episome epigenetic landscapes in primary NPC tissue.

Original languageEnglish (US)
Pages (from-to)9683-9688
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number36
DOIs
StatePublished - Sep 5 2017
Externally publishedYes

Bibliographical note

Funding Information:
ACKNOWLEDGMENTS. We thank Dr. Zhen Lin (Tulane University) for the Akata EBV annotation gtf file. B.Z. is supported by National Institute of Allergy and Infectious Diseases Grant R01AI123420; E.K. is supported by National Cancer Institute Grants R01CA047006, R01CA170023, and R01CA085180; X.G. is supported by International Cooperation Project of Science and Technology Plan of Guangdong Province 2014A050503033 and 2016A050502011; P.B. is supported by the Bristol-Myers Squibb Foundation for Immunology Research (2017); and M.Z. is supported by National Natural Science Foundation of China Grant 81520108022.

Publisher Copyright:
© 2017, National Academy of Sciences. All rights reserved.

Keywords

  • Epstein–Barr virus
  • ETV6
  • H3K27ac
  • Nasopharyngeal carcinoma
  • Super-enhancer

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