Super-Enhancers Promote Transcriptional Dysregulation in Nasopharyngeal Carcinoma [ChIP-seq]

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 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE95749 | GEO | 2017/12/01

SECONDARY ACCESSION(S): PRJNA378260

REPOSITORIES: GEO