Enhancer hijacking HELLS promotes macrophage M2 polarization results in poor prognosis for prostate cancer patients

Cancer genome frequently carry large-scale somatic structural variations (SVs). The altered 3D genome structure has been identified as a potential mechanism for oncogene activation. Recently, it has been reported that enhancer hijacking events are involved in cancer progress. However, the underlying regulatory effect of non-coding large-scale somatic SVs on proto-oncogene activation in prostate cancer (PCa) remain unclear. Here, we screened enhancer hijacking events in PCa and validated them using CRISPR knockout and fluorescence in situ hybridization experiments. The functional roles of these events in PCa were investigated through cell proliferation analysis, wound-healing assay, Transwell assay, flow cytometry, immunohistochemical staining, animal experiment and bioinformatics analysis. HELLS was identified not only as a prognosis-related gene in PCa but also due to its involvement in an enhancer-hijacking event. The enhancer hijacking drives ectopic expression of HELLS, which promotes malignant phenotype of PCa cells, such as cell proliferation and migration. Meanwhile, HELLS expression levels were positively correlated with tumor neoantigen and mutation burden, Gleason score, pathological stage (T and N stage), prostate-specific antigen (PSA), and neural/vascular invasion in PCa patients. Moreover, HELLS expression varied across immune subtypes in PCa tissues, with particularly high expression in macrophages. Compared to para-cancerous or prostate hyperplasia tissues, HELLS was highly expressed in PCa tissues. It was especially highly expressed in the nucleus of M2 macrophages and co-expressed with M2 macrophage marker CD163 in PCa tissues. Furthermore, enhancer hijacking of HELLS promotes immune infiltration levels and macrophage M2 polarization in PCa. Hence, our findings indicated that enhancer hijacking drives ectopic expression of HELLS, which promotes macrophage M2 polarization, resulting in PCa progression. The hijacked enhancer for HELLS could serve as a novel early genetic indicator for PCa patients.