Figure 5.

OC2 promotes neuroendocrine features through super-enhancer reprogramming. (A) OC2 signature genes derived from AR-dependent LNCaP cells (Left). And the Gene Set enrichment analysis of OC2 signature genes (Right). (B) Enforced OC2 expression upregulates multiple NE signature genes in LNCaP cells. Non-expressing genes were removed from the heatmap. (C) SYP IHC staining in LNCaP Vec Con and OC2 OE cells xenograft models. (D) Genes proximal to super-enhancer regions identified as newly formed in OC2 OE cells versus control cells with corresponding change in RNA level. (E) Visualization of H3K27Ac signals around TMPRSS2 / FOLH1 (encoding PSMA) and SRRM4 / CLIP2 are shown. (F) Integrated HiC and H3K27Ac signal showed enhancers looped to promoter loci of TMPRSS2 and SRRM4. (G) Expression of TMPRSS2 and SRRM4 in SU2C cohorts stratified by OC2 activity. (H) Upregulation of the splicing factor SRRM4 promotes neural-specific splicing variants with OC2 overexpression (unpaired two-tailed Student's t-test, **P < 0.01, *P< 0.05). (I) Master neuronal suppressor REST was suppressed in the nucleus (middle) through SRRM4-mediated spicing variant REST4 (left), which promotes NE differentiation (right).