Super-enhancers promote transcriptional dysregulation in nasopharyngeal carcinoma

Jiang Yuan, Yan Yi Jiang, Anand Mayakonda, Moli Huang, Ling Wen Ding, Han Lin, Fenggang Yu, Yanan Lu, Thomas Kwok Seng Loh, Marilynn Chow, Samantha Savage, Jeffrey Tyner, De Chen Lin, H. Phillip Koeffler

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

Nasopharyngeal carcinoma (NPC) is an invasive cancer with particularly high incidence in Southeast Asia and Southern China. The pathogenic mechanisms of NPC, particularly those involving epigenetic dysregulation, remain largely elusive, hampering clinical management of this malignancy. To identify novel druggable targets, we carried out an unbiased high-throughput chemical screening and observed that NPC cells were highly sensitive to inhibitors of cyclin-dependent kinases (CDK), especially THZ1, a covalent inhibitor of CDK7. THZ1 demonstrated pronounced antineoplastic activities both in vitro and in vivo. An integrative analysis using both whole-transcriptome sequencing and chromatin immunoprecipitation sequencing pinpointed oncogenic transcriptional amplification mediated by super-enhancers (SE) as a key mechanism underlying the vulnerability of NPC cells to THZ1 treatment. Further characterization of SE-mediated networks identified many novel SE-associated oncogenic transcripts, such as BCAR1, F3, LDLR, TBC1D2, and the long noncoding RNA TP53TG1. These transcripts were highly and specifically expressed in NPC and functionally promoted NPC malignant phenotypes. Moreover, DNA-binding motif analysis within the SE segments suggest that several transcription factors (including ETS2, MAFK, and TEAD1) may help establish and maintain SE activity across the genome. Taken together, our data establish the landscape of SE-associated oncogenic transcriptional network in NPC, which can be exploited for the development of more effective therapeutic regimens for this disease.

Original languageEnglish (US)
Pages (from-to)6614-6626
Number of pages13
JournalCancer Research
Volume77
Issue number23
DOIs
Publication statusPublished - Dec 1 2017

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Yuan, J., Jiang, Y. Y., Mayakonda, A., Huang, M., Ding, L. W., Lin, H., ... Koeffler, H. P. (2017). Super-enhancers promote transcriptional dysregulation in nasopharyngeal carcinoma. Cancer Research, 77(23), 6614-6626. https://doi.org/10.1158/0008-5472.CAN-17-1143