GSE95749
Super-Enhancers Promote Transcriptional Dysregulation in  Nasopharyngeal Carcinoma [ChIP-seq]
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 the 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 cyclin-dependent kinases (CDKs) inhibitors,  especially THZ1, a covalent inhibitor of CDK7. THZ1 demonstrated pronounced  anti-neoplastic activities both in vitro and in vivo. An integrative analysis using both  whole-transcriptome sequencing (RNA-Seq) and chromatin-immunoprecipitation  sequencing (ChIP-Seq) pinpointed oncogenic transcriptional amplification mediated  by Super-Enhancer (SE) as a key mechanism underlying the vulnerability of NPC  cells to THZ1 treatment. Further characterization of SE-mediated network identified  many novel SE-associated oncogenic transcripts, such as BCAR1, F3, LDLR,  TBC1D2 and a long non-coding 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. Our data together established the landscape  of SE-associated oncogenic transcriptional network in NPC, which can be exploited  for the development of more effective therapeutic regimen for this disease. Overall design: ChIP seq for histone modifications in three NPC cell lines – C666-1, HK1 and HNE1