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Aberrant super-enhancer landscape in enzalutamide-resistant prostate cancer cells

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE228308 | GEO | 2025/03/24

REPOSITORIES: GEO

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Project description:Enzalutamide (ENZ) is a potent androgen receptor (AR) antagonist with activity in castration-resistant prostate cancer (CRPC); however, progression to ENZ-resistant (ENZ-R) CRPC frequently occurs with rising serum PSA levels, implicating AR full length (ARFL) or variants (AR-Vs) in disease progression. To define functional roles of ARFL and AR-Vs in ENZ-R CRPC, we designed 3 antisense oligonucleotides (ASO) targeting exon 1, intron 1, and exon 8 in AR pre-mRNA to knockdown either ARFL alone, or ARFL plus AR-Vs, and examined their respective effects in LNCaP-derived ENZ-R, as well as M12 and 22Rv1, cells. ENZ-R LNCaP xenografts express high levels of both ARFL and AR-V7 compared to CRPC LNCaP xenografts. In particular, ARFL levels were ~20-fold higher than AR-V7. ENZ-R LNCaP sub-lines, derived by selection from the ENZ xenografts, also expressed uniformly high levels of ARFL and AR-V7 compared to CRPC LNCaP cells. In addition, both ARFL and AR-V7 are highly expressed in the nuclear fractions of ENZ-R-LNCaP. In ENZ-R LNCaP cells, knockdown of ARFL alone, or ARFL plus AR-Vs, similarly induced apoptosis, suppressed cell growth and AR-regulated gene expression in vitro, and delayed tumour growth in vivo. In 22Rv1 cells that are inherently resistant to ENZ, knockdown of both ARFL and AR-Vs more potently suppressed cell growth, AR transcriptional activity and AR-regulated gene expression than knockdown of ARFL alone. These data indicate the AR is an important driver of ENZ resistance, and while the contributions of ARFL and AR-Vs can vary across cell systems, ARFL is the key driver in the ENZ-R LNCaP model. AR targeting strategies against both ARFL and AR-Vs is a rational approach for AR-dependent CRPC. CRPC and ENZ-R LNCaP xenografts were generated as described in: Gleave, M.E., et al., Serum prostate specific antigen levels in mice bearing human prostate LNCaP tumors are determined by tumor volume and endocrine and growth factors. Cancer Res, 1992. 52(6): p. 1598-605.

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Aberrant super-enhancer landscape in enzalutamide-resistant prostate cancer cells

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