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Androgen-Responsive Genes in Prostate Cancer pp 85–100Cite as

Mechanisms of ARE-Independent Gene Activation by the Androgen Receptor in Prostate Cancer Cells: Potential Targets for Better Intervention Strategies

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Abstract

Molecular mechanisms that redirect androgen or AR action to primarily support growth in prostate cancer (PC) cells are not adequately understood. In PC cells in which AR supports robust cell growth in the absence of hormone, AR is localized in the nucleus independent of hormone; still, in these cells androgen is required for activation of its classical target genes that involves AR binding to canonical or noncanonical androgen response elements (AREs). However, following either hormone-dependent or -independent nuclear translocation, AR activates a distinct set of critical growth genes in a ligand-insensitive manner through putative tethered associations of AR with chromatin. Consistent with these observations, splice variants of AR that lack the ligand binding domain support PC growth by activating a transcriptional program distinct from that induced by androgen plus full length AR. Indeed, several studies suggest that specific AR tethering proteins help to redirect AR toward targeting gene sets appropriate to the physiological context. These proteins may also simultaneously suppress the activation of other genes by AR. This review describes how transcriptional signaling by AR is directed by other chromatin bound transcription factors, comprising the AR “tetherome,” that could work either in concert with AREs or completely independent of them. The potential utility of specific tether-dependent growth signaling mechanisms of AR as tumor-selective drug targets in both early stage and advanced prostate cancer is discussed.

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Authors and Affiliations

  1. Barbara Ann Karmanos Cancer Institute, 4100 John R, HWRC Room 840.1, Detroit, MI, 48201, USA

    Manohar Ratnam

  2. Barbara Ann Karmanos Cancer Institute, 4100 John R, Detroit, MI, 48201, USA

    Mugdha Patki

  3. Laboratory of Cancer Prevention, National Cancer Institute, Frederick, MD, 21702, USA

    Mesfin Gonit

  4. Bioinformatics, Proteomics and Genomics, University Medical Center, Toledo, OH, 43614, USA

    Robert Trumbly

  5. Department of Biochemistry and Cancer Biology, University Medical Center, Toledo, OH, 43614, USA

    Robert Trumbly

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  2. Mugdha Patki
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Correspondence to Manohar Ratnam .

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  1. , Shadyside Medical Center, University of Pittsburgh, Centre Ave 5200, Pittsburgh, 15232, Pennsylvania, USA

    Zhou Wang

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Ratnam, M., Patki, M., Gonit, M., Trumbly, R. (2013). Mechanisms of ARE-Independent Gene Activation by the Androgen Receptor in Prostate Cancer Cells: Potential Targets for Better Intervention Strategies. In: Wang, Z. (eds) Androgen-Responsive Genes in Prostate Cancer. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-6182-1_6

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