Inhibition of the Acetyltransferases p300 and CBP Reveals a Targetable Function for p300 in the Survival and Invasion Pathways of Prostate Cancer Cell Lines

Department of Urology, Experimental Urology, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria.
Molecular Cancer Therapeutics (Impact Factor: 6.11). 06/2011; 10(9):1644-55. DOI: 10.1158/1535-7163.MCT-11-0182
Source: PubMed

ABSTRACT Inhibitors of histone deacetylases have been approved for clinical application in cancer treatment. On the other hand, histone acetyltransferase (HAT) inhibitors have been less extensively investigated for their potential use in cancer therapy. In prostate cancer, the HATs and coactivators p300 and CBP are upregulated and may induce transcription of androgen receptor (AR)-responsive genes, even in the absence or presence of low levels of AR. To discover a potential anticancer effect of p300/CBP inhibition, we used two different approaches: (i) downregulation of p300 and CBP by specific short interfering RNA (siRNA) and (ii) chemical inhibition of the acetyltransferase activity by a newly developed small molecule, C646. Knockdown of p300 by specific siRNA, but surprisingly not of CBP, led to an increase of caspase-dependent apoptosis involving both extrinsic and intrinsic cell death pathways in androgen-dependent and castration-resistant prostate cancer cells. Induction of apoptosis was mediated by several pathways including inhibition of AR function and decrease of the nuclear factor kappa B (NF-κB) subunit p65. Furthermore, cell invasion was decreased upon p300, but not CBP, depletion and was accompanied by lower matrix metalloproteinase (MMP)-2 and MMP-9 transcriptions. Thus, p300 and CBP have differential roles in the processes of survival and invasion of prostate cancer cells. Induction of apoptosis in prostate cancer cells was confirmed by the use of C646. This was substantiated by a decrease of AR function and downregulation of p65 impairing several NF-κB target genes. Taken together, these results suggest that p300 inhibition may be a promising approach for the development of new anticancer therapies.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Gene expression is dynamically controlled by epigenetics through post-translational modifications of histones, chromatin-associated proteins and DNA itself. All these elements are required for the maintenance of chromatin structure and cell identity in the context of a normal cellular phenotype. Disruption of epigenetic regulation is a common event in human cancer. Here, we review the key protein families that arbitrate epigenetic signaling through writing, erasing or reading specific post-translational modifications. By exploiting the leading role of epigenetics in tumor development and the reversibility of epigenetic modifications, promising novel epigenetic-based therapies are being developed. In this article, we highlight the emerging small-molecule inhibitors targeting each class of chromatin-associated protein, their current use in preclinical and clinical trials and their perspectives for being approved in the near future.
    British Journal of Pharmacology 07/2014; 172(11). DOI:10.1111/bph.12844 · 4.99 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Three decades of research into p300/CBP, since the first report in 1985, have revealed its importance to normal cell health and etiology of disease. p300/CBP is a key enzyme in higher eukaryotes, where it acts as an effector in myriad major cellular signaling pathways, which modulate protein functions and gene expression in response to a variety of signals. This is accomplished by binding of over 400 protein ligands to its various protein interaction-mediating domains and the acetylation of ∼100 protein substrates. The unusual hit-and-run kinetic mechanism has permitted the identification of p300/CBP-specific acetyltransferase inhibitors, which have shown promising effects in studies in living cells. The protein acetylation and protein binding functions of p300/CBP are intricately interrelated, and both are targets of pharmacological interventions that may have considerable therapeutic applications.
    Chemical Reviews 01/2015; 115(6). DOI:10.1021/cr500452k · 45.66 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: EP300 gene encoding p300 is a candidate tumor suppressor gene. This study investigated p300 expression and gene alteration in oral squamous cell carcinoma (OSCC) specimens to assess its role in OSCC development.
    Journal of Oral Pathology and Medicine 08/2014; 44(3). DOI:10.1111/jop.12227 · 1.87 Impact Factor