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Cancer Res. 2017 Dec 1;77(23):6614-6626. doi: 10.1158/0008-5472.CAN-17-1143. Epub 2017 Sep 26.

Super-Enhancers Promote Transcriptional Dysregulation in Nasopharyngeal Carcinoma.

Author information

1
Cancer Science Institute of Singapore, National University of Singapore, Singapore.
2
Cancer Science Institute of Singapore, National University of Singapore, Singapore. csijy@nus.edu.sg De-Chen.Lin@cshs.org.
3
Department of Otolaryngology, National University Hospital Singapore, Singapore.
4
National University Cancer Institute of Singapore, National University Health System, Singapore.
5
Department of Cell, Developmental & Cancer Biology, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon.
6
Department of Medicine, Cedars-Sinai Medical Center, University of California, Los Angeles School of Medicine, Los Angeles, California.
7
National University Cancer Institute, National University Hospital Singapore, Singapore.

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. Cancer Res; 77(23); 6614-26. ©2017 AACR.

PMID:
28951465
DOI:
10.1158/0008-5472.CAN-17-1143
[Indexed for MEDLINE]
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