Characterization of Cancer Hallmark Enhancer RNA Uncovers Novel Strategies for Precision Oncology

Enhancer RNAs (eRNAs) play crucial roles in regulating cancer progression and serve as clinical biomarkers or therapeutic targets. However, systematic identification of oncogenic eRNAs and strategies to target them for precision oncology remain largely unexplored. In this study, we comprehensively identified tens of thousands of eRNAs significantly associated with cancer hallmark signatures across diverse tumor types, which we defined as hallmark eRNAs. These eRNAs exhibit a strong capacity to promote specific cancer hallmarks by mediating distinct oncogenic pathways in a cancer type-dependent manner. We also found that RNA-binding proteins can directly bind to eRNAs to regulate tumorigenesis. By integrating regulator-eRNA networks with drug response data, we identified drugs that target different cancer processes with specific associations to hallmark eRNAs. Specifically, in liver hepatocellular carcinoma, we characterized a hallmark eRNA, ADAMTS5e, which can activate the expression of oncogene ADAMTS5 to promote metastasis in vivo and in vitro. Cancer cells with high ADAMTS5e expression are resistant to sorafenib but are sensitive to the combination treatment of sorafenib and docetaxel, or sorafenib and navitoclax. Our study developed a platform to identify cancer-hallmark eRNAs and provided promising drug screening strategies. This approach was exemplified by the functional characterization of ADAMTS5e in cancer metastasis and the discovery of an effective combinational treatment. Together, these findings highlight the potential of hallmark eRNAs in precision oncology.