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Identification of HOXB13 binding sites in metastatic PC treated with Enzalutamide

ABSTRACT: HOXB13 is a developmentally regulated transcription factor, co-expressed along with the Androgen receptor (AR) in a majority of PCs. Previous studies have indicated context dependent roles of HOXB13 in the functional regulation of AR and enrichment of HOXB13 motifs in the AR cistrome. Our studies showed that genetic or pharmacological blockade of HOXB13 sensitized mCRPCs to Enzalutamide (ENZ, Xtandi), an anti-androgen that is currently deployed to treat mCRPC patients. To identify HOXB13-mediated mechanism of castration-resistance ChIP-sequencing was performed with the HOXB13-K13ac, or IgG antibodies in the metastatic prostate cancer cell line, C4-2B in vehicle treated as well as Enzalutamide treated cell lines. We demonstrated for the first time that BRD4, epigenetically regulates HOXB13 gene expression in PCs. Consistently, JQ1 the prototype BET inhibitor suppresses HOXB13 expression and inhibit mCRPC growth. ChIP-sequence analysis reveals that HOXB13 recruitment to the chromatin is not completely abrogated in Enzalutamide treated cells identify a subset of genes that may have potential role in CRPC proliferation, anti-androgen resistance and metastasis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE125902 | GEO | 2022/01/30

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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Identification of HOXB13 binding sites in metastatic PC treated with Enzalutamide

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