Aberrant super-enhancer landscape in enzalutamide-resistant prostate cancer cells
Background: Castration-resistant prostate cancer (CRPC), which has developed resistance to next-generation antiandrogens such as enzalutamide (Enz), is a lethal disease. Furthermore, transcriptional regulation by super enhancers (SEs) are crucial for the growth and spread of prostate cancer, as well as drug resistance. The functions of SEs, a significant class of noncoding DNA cis-regulatory elements, have been the subject of numerous recent studies in the field of cancer research.  Methods: The goal of this research was to identify SEs associated with Enz resistance in C4-2B cells using chromatin immunoprecipitation-sequencing and cleavage under targets and tagmentation (CUT&Tag). Using HOMER analysis to predict protein-gene binding motifs, we identified master transcription factors (TFs) that may bind to SE sites. Using small interfering RNA, WST-1 assays, and qRT-PCR, we then confirmed the associations between TFs of SEs and Enz resistance.  Results: 999 SEs were screened from C4-2B EnzR cells in total. Incorporating analysis with RNA-seq data revealed 46 SEs to be strongly associated with the promotion of Enz resistance. Additionally, we finally predicted that master TFs bind to SEs binding regions. Subsequently, we selected zinc finger protein 467 (ZFP467) and SMAD family member 3 (SMAD3) to confirm the functional connections of master TFs with Enz resistance via SEs (ZNF467).   Conclusions: In this study, SMAD3 and ZNF467 found to be closely related to Enz-resistant in CRPC. Our research uncovered a sizable group of SEs linked to Enz resistance in prostate cancer, dissected the mechanisms underlying SE Enz resistance, and shed light on potential clinical uses for SEs. Overall design: The super enhancers of C42B enzalutamide-resistant prostate cancer cell lines were analyzed by CUT & Tag sequencing.