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Int. J. Mol. Sci. 2017, 18(7), 1449; doi:10.3390/ijms18071449

Differential Effects of Histone Acetyltransferase GCN5 or PCAF Knockdown on Urothelial Carcinoma Cells

Department of Urology, Heinrich Heine University, 40225 Düsseldorf, Germany
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Received: 23 May 2017 / Revised: 26 June 2017 / Accepted: 28 June 2017 / Published: 5 July 2017
(This article belongs to the Special Issue Molecular Research on Urology)
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Abstract

Disturbances in histone acetyltransferases (HATs) are common in cancers. In urothelial carcinoma (UC), p300 and CBP are often mutated, whereas the GNAT family HATs GCN5 and PCAF (General Control Nonderepressible 5, p300/CBP-Associated Factor) are often upregulated. Here, we explored the effects of specific siRNA-mediated knockdown of GCN5, PCAF or both in four UC cell lines (UCCs). Expression of various HATs and marker proteins was measured by qRT-PCR and western blot. Cellular effects of knockdowns were analyzed by flow cytometry and ATP-, caspase-, and colony forming-assays. GCN5 was regularly upregulated in UCCs, whereas PCAF was variable. Knockdown of GCN5 or both GNATs, but not of PCAF alone, diminished viability and inhibited clonogenic growth in 2/4 UCCs, inducing cell cycle changes and caspase-3/7 activity. PCAF knockdown elicited GCN5 mRNA upregulation. Double knockdown increased c-MYC and MDM2 (Mouse Double Minute 2) in most cell lines. In conclusion, GCN5 upregulation is especially common in UCCs. GCN5 knockdown impeded growth of specific UCCs, whereas PCAF knockdown elicited minor effects. The limited sensitivity towards GNAT knockdown and its variation between the cell lines might be due to compensatory effects including HAT, c-MYC and MDM2 upregulation. Our results predict that developing drugs targeting individual HATs for UC treatment may be challenging. View Full-Text
Keywords: histone acetyltransferases; urothelial carcinoma; bladder cancer; GCN5; PCAF; p300; CBP; MDM2; c-MYC; epigenetic drugs histone acetyltransferases; urothelial carcinoma; bladder cancer; GCN5; PCAF; p300; CBP; MDM2; c-MYC; epigenetic drugs
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Koutsogiannouli, E.A.; Wagner, N.; Hader, C.; Pinkerneil, M.; Hoffmann, M.J.; Schulz, W.A. Differential Effects of Histone Acetyltransferase GCN5 or PCAF Knockdown on Urothelial Carcinoma Cells. Int. J. Mol. Sci. 2017, 18, 1449.

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