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Increased chromatin accessibility drives transition to androgen receptor splice variant dependence in castration-resistant prostate cancer II

ABSTRACT: Androgen receptor (AR) splice variants, of which ARv7 is most common, are increased in prostate cancer (PC) that develops resistance to androgen signaling inhibitor drugs, but the extent to which they drive AR activity, and whether they have novel functions or dependencies, remain to be determined. We generated a subline of VCaP PC cells (VCaP16) that was resistant to the AR inhibitor enzalutamide (ENZ) and found that AR activity was independent of the full length AR (ARfl), despite its continued high level expression, and was instead driven by ARv7. The ARv7 cistrome and transcriptome in these cells mirrored that of the ARfl in VCaP cells, although ARv7 chromatin binding was weaker, and strong ARv7 binding sites correlated with higher affinity ARfl binding sites across multiple models and clinical samples. Notably, although ARv7 expression increased rapidly in response to ENZ, there was a long lag before it gained chromatin binding and transcriptional activity. This lag was associated with an increase in chromatin accessibility, with the AR and nuclear factor I (NFI) motifs being most enriched at these more accessible sites. Moreover, the transcriptional effects of combined NFIB and X knockdown versus ARv7 knockdown were highly correlated. These findings indicate that ARv7 can drive the AR program, but that its activity is dependent on adaptations that increase chromatin accessibility to enhance its intrinsically weak chromatin binding.

ORGANISM(S): Homo sapiens

PROVIDER: GSE277606 | GEO | 2025/01/01

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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Increased chromatin accessibility drives transition to androgen receptor splice variant dependence in castration-resistant prostate cancer II

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