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Sequence specific suppression of androgen receptor-DNA binding in vivo by a Py-Im polyamide.

ABSTRACT: The crucial role of androgen receptor (AR) in prostate cancer development is well documented, and its inhibition is a mainstay of prostate cancer treatment. Here, we analyze the perturbations to the AR cistrome caused by a minor groove binding molecule that is designed to target a sequence found in a subset of androgen response elements (ARE). We find treatment with this pyrrole-imidazole (Py-Im) polyamide exhibits sequence selectivity in its repression of AR binding in vivo. Differentially changed loci are enriched for sequences resembling ARE half-sites that match the Py-Im polyamide binding preferences determined in vitro. Comparatively, permutations of the ARE half-site bearing single or double mismatches to the Py-Im polyamide binding sequence are not enriched. This study confirms that the in vivo perturbation pattern caused by a sequence specific polyamide correlates with its in vitro binding preference genome-wide in an unbiased manner.

SUBMITTER: Kurmis AA

PROVIDER: S-EPMC6486638 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Sequence specific suppression of androgen receptor-DNA binding in vivo by a Py-Im polyamide

Project description:The crucial role of androgen receptor in prostate cancer development is well documented, and its inhibition is a mainstay of prostate cancer treatment. Here we analyze the perturbations to the androgen receptor cistrome caused by a minor groove binding molecule that is designed to target a sequence found in a subset of androgen response elements. We find treatment with this pyrrole-imidazole polyamide exhibits sequence selectively in its repression of androgen receptor binding in vivo. Differentially changed loci are enriched for sequences resembling ARE half-sites that match the Py-Im polyamide binding preferences determined in vitro. Comparatively, permutations of ARE half-site bearing single or double mismatches to the Py-Im polyamide binding sequence are not enriched. This study represents an indirect determination of Py-Im polyamide binding preference in vivo using an unbiased approach.

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Sequence specific suppression of androgen receptor-DNA binding in vivo by a Py-Im polyamide

Project description:Sequence specific suppression of androgen receptor-DNA binding in vivo by a Py-Im polyamide

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Suppression of androgen receptor-mediated gene expression by a sequence-specific DNA-binding polyamide.

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An HRE-Binding Py-Im Polyamide Impairs Hypoxic Signaling in Tumors.

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| S-EPMC3814215 | biostudies-literature

Suppression of androgen receptor mediated gene expression by a sequence-specific DNA binding polyamide

Project description:Androgen Receptor (AR) is essential for the growth and progression of prostate cancer in both hormone-sensitive and hormone-refractory disease. We have designed a sequence-specific DNA binding polyamide (1) that targets the consensus androgen response element (ARE). This polyamide binds the PSA promoter ARE, inhibits androgen-induced expression of PSA and several other AR-regulated genes in cultured prostate cancer cells, and reduces AR occupancy at the PSA promoter and enhancer. Down-regulation of PSA by this polyamide was comparable to that produced by the synthetic anti-androgen bicalutamide (Casodex) at the same concentration. Genome-wide expression analysis reveals that a similar number of transcripts are affected by treatment with the polyamide and with bicalutamide. Direct inhibition of AR-DNA binding by sequence-specific DNA binding small molecules could offer an alternative approach to antagonizing AR activity. A polyamide (2) that targets a different DNA sequence is included as a control. Keywords: Gene expression changes in cultured LNCaP cells after DHT-stimulation and various treatment conditions

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Structural basis for cyclic Py-Im polyamide allosteric inhibition of nuclear receptor binding.

Project description:Pyrrole-imidazole polyamides are a class of small molecules that can be programmed to bind a broad repertoire of DNA sequences, disrupt transcription factor-DNA interfaces, and modulate gene expression pathways in cell culture experiments. In this paper we describe a high-resolution X-ray crystal structure of a β-amino turn-linked eight-ring cyclic Py-Im polyamide bound to the central six base pairs of the sequence d(5'-CCAGTACTGG-3')(2), revealing significant modulation of DNA shape. We compare the DNA structural perturbations induced by DNA-binding transcripton factors, androgen receptor and glucocorticoid receptor, in the major groove to those induced by cyclic polyamide binding in the minor groove. The cyclic polyamide is an allosteric modulator that perturbs the DNA structure in such a way that nuclear receptor protein binding is no longer compatible. This allosteric perturbation of the DNA helix provides a molecular basis for disruption of transcription factor-DNA interfaces by small molecules, a minimum step in chemical control of gene networks.

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