Aberrant super‐enhancer landscape in human hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) cells exploit an aberrant transcriptional program to sustain their infinite growth and progression. Emerging evidence indicates that the continuous and robust transcription of oncogenes in cancer cells is often driven by super‐enhancers (SEs). In this study, we systematically compared the SE‐landscapes between normal liver and HCC cells and revealed that the cis‐acting SE‐landscape was extensively reprogrammed during liver carcinogenesis. HCC cells acquired SEs at multiple prominent oncogenes to drive their vigorous expression. We identified SPHK1 as a novel SE‐associated oncogene, and we used this gene as an example to illustrate the impact of SEs on the activation of oncogenes in HCC. Concurrently, we also showed that the critical components of the trans‐acting SE‐ complex, namely, CDK7, BRD4, EP300, and MED1, were frequently overexpressed in human HCCs and were associated with the poor prognosis of HCC patients. Using the CRISPR/Cas9 gene editing system and specific small molecular inhibitors, we further demonstrated that HCC cells were highly sensitive to perturbations of the SE‐complex. The inactivation of CDK7, BRD4, EP300, and MED1 selectively repressed the expression of SE‐associated oncogenes in HCC. Finally, we demonstrated that THZ1, which is a small molecule inhibitor of CDK7, exerted a prominent anti‐cancer effect in both in vitro and in vivo HCC models.

Conclusions

The SE landscape and machinery were significantly altered in human HCCs. HCC cells are highly susceptible to perturbations of the SE complex due to the resulting selective suppression of SE‐associated oncogenes. Our results suggest that targeting SE‐complex is a promising therapeutic strategy for HCC treatment.

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