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AHR plays important roles in mediating diverse responses to Enzalutamide in prostate cancer

ABSTRACT: Enzalumatide (ENZ) is a widely used second generation nonsteroidal Androgen Receptor inhibitor that is integral in managing castration-resistant prostate cancer (CRPC). However, resistance inevitably develops in months and limits the clinical benefits of ENZ. AHR is commonly upregulated in ENZ-resistant (ENZR) cell lines and is essential for ENZR CRPC growth in vitro and in vivo. Interestingly, the canonical AHR xenobiotic pathway does not seem to play a role. To characterize, for the first time, transcriptional targets of AHR in prostate cancer, we performed ChIP-seq of AHR and H3K9ac, a marker of active chromatin, in CWR-R1ENZR cells. An AHR knockdown cell line is also included to identify the difference of AHR trancriptional action. ChIP-seq results revealed that AHR binds to multiple genes targeted by AR and glucocorticoid receptor (GR), a well-established mechanism bypassing the AR blockade of ENZ. Furthermore, AHR also binds to many marker genes of neuroendocrine (NE) differentiation, a feature indicating AR-independence and clinical aggressiveness in prostate cancer. Together, these results depict AHR as an important regulator of reponses to ENZ in CRPC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE289313 | GEO | 2026/02/28

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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AHR plays important roles in mediating diverse responses to Enzalutamide in prostate cancer

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