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A Novel Peptide Encoded by circSRCAP Confers Resistance to Enzalutamide by Inhibiting the Ubiquitin-Dependent Degradation of AR-V7 in Castration-Resistant Prostate Cancer

ABSTRACT: Background: The sustained activation of androgen receptor splice variant-7 (AR-V7) is a key factor in the resistance of castration-resistant prostate cancer (CRPC) patients to second-generation anti-androgen (AR) drugs such as enzalutamide (ENZ). The AR/AR-V7 protein is regulated by the E3 ubiquitin ligase STUB1 and a protein complex formed by HSP70. However, the specific mechanism remains elusive. Methods: High-throughput RNA sequencing was employed to detect differentially expressed circular RNAs (circRNAs) in ENZ-resistant and control CRPC cells. The coding potential of circSRCAP was identified through polysome profiling and LC-MS. The function of circSRCAP was validated in vitro and in vivo via gain or loss of function assays. Mechanistic insights were derived from immunoprecipitation analyses. Results: A novel ENZ-resistant circular RNA (circRNA) named circSRCAP has been identified, showing upregulation in ENZ-resistant C4-2B cells (ENZR-C4-2B) and correlation with elevated protein levels of AR-V7. circSRCAP undergoes cleavage into a loop by the splicing factor EIF4A3 and is derived from the nucleus by the RNA helicase DDX39A. Mechanistically, circSRCAP encodes a 75 amino acid peptide, circSRCAP-75aa, which inhibits the ubiquitination of the AR/AR-V7's co-chaperone protein HSP70 by dissociating STUB1, a ubiquitin E3 ligase. This process leads to the upregulation of AR-V7 protein expression, thereby promoting resistance of castration-resistant prostate cancer (CRPC) cells to ENZ. Xenograft tumor models further confirm the role of circSRCAP in CRPC progression and its potential as a therapeutic target for ENZ-resistant CRPC (ENZR-CRPC). Conclusions: circSRCAP presents an epigenetic mechanism that sheds light on the fate determination of AR-V7, offering a promising therapeutic target for the treatment of ENZR-CRPC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE264133 | GEO | 2025/01/29

REPOSITORIES: GEO

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	GSE264133_circRNA_raw_count.txt.gz	Txt

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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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A Novel Peptide Encoded by circSRCAP Confers Resistance to Enzalutamide by Inhibiting the Ubiquitin-Dependent Degradation of AR-V7 in Castration-Resistant Prostate Cancer

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