Super-Enhancers Promote Transcriptional Dysregulation in Nasopharyngeal Carcinoma

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 and 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. .

Predicting master transcription factors from pan-cancer expression data

“…SOX10 is important for melanoma cell proliferation and survival and is associated with SEs in melanoma tissues (Eliades et al, 2018). TP63 is a known master regulator of keratinocyte differentiation and associated with SEs in esophageal squamous cells (Yuan et al, 2017). By analyzing publicly available H3K27ac data, we confirmed that POU2AF1, SOX10, and TP63 are associated with SEs in DLBC, primary melanoma tissues, and an esophageal squamous cell carcinoma cell line, respectively ( Figure 1B, Figure S1A).…”

“…Lineage-specific oncogenic transcription factors often share features attributed to MTFs, including association with SEs (Chapuy et al, 2013;Eliades et al, 2018;Shang et al, 2019;Yuan et al, 2017). Among these include POU2AF1 (OCA-B) in diffuse large B-cell lymphoma (DLBC) (Chapuy et al, 2013), SOX10 in melanoma (SKCM) (Eliades et al, 2018), and TP63 in esophageal squamous carcinoma (ESSC) (Yuan et al, 2017). POU2AF1 is critical for B-cell fate determination and was found proximal to especially large BRD4loaded SEs in DLBC cells (Chapuy et al, 2013).…”

“…This analysis demonstrates that TFs with high CaCTS ranks tend to be enriched for SE-associated factors in these twenty tumor types and suggests that bona fide MTFs are likely present among high CaCTS scoring factors in the 14 tumor types where enhancer data was not available. We noted that most known candidate factors were among the top 5% of expressed factors in the relevant tumor type (Chapuy et al, 2013;Eliades et al, 2018;Yuan et al, 2017). Therefore, to arrive at a collection of candidate MTFs, we retrieved those factors with high CaCTS scores (top 5%; CaCTS rank ≤ 79) that were also highly expressed (within the top 5% of expression; expression rank ≤ 79) for each of the 34 tumor types (Table S6, Figure S1C).…”

TP63, SOX2 and KLF5 Establish Core Regulatory Circuitry and Construct Cancer Specific Epigenome in Esophageal Squamous Cell Carcinoma

“…These epigenetic characteristics are also notably altered in disease states, such as cancer. In particular, we and others have shown that the clusters of active enhancers called super-enhancers (SEs) mediate transcriptional dysregulation in human cancers (Chipumuro et al, 2014;Hnisz et al, 2013;Jiang et al, 2017;Xie et al, 2018;Yuan et al, 2017). These SE loci are occupied by high density of lineage-or cell type-specific transcription factors (TFs), chromatin regulators and coactivators to govern gene expression networks and hence contribute profoundly to cancer biology Hnisz et al, 2017;Whyte et al, 2013).…”

“…Both BET and HDAC inhibitors display promising anticancer potential in various types of malignancies through perturbation of multiple components in transcriptional regulation, most notably SEs (Greer et al, 2015;Ott et al, 2018;Ozer et al, 2018;Qu et al, 2017). Specifically, cancer-specific SEs exhibit hypersensitivity to transcriptional inhibition, a primary mechanism underlying the superior anti-tumor potency of BET and HDAC inhibitors (Chapuy et al, 2013;Hnisz et al, 2017;Jiang et al, 2017;Loven et al, 2013;Ott et al, 2018;Yuan et al, 2017).…”