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Carcinogenesis Advance Access published online on January 6, 2009
Carcinogenesis, doi:10.1093/carcin/bgp005
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Elevated NCOR1 disrupts a network of dietary-sensing nuclear receptors in bladder cancer cells

S. Asad Abedina, James L. Thornea, Sebastiano Battagliaa, Orla Maguireb, Laura Hornungb, Alan P. Dohertyc, Ian G. Millsd and Moray J. Campbellb,e

a Institute of Biomedical Research, Wolfson Drive, University of Birmingham Medical School, Edgbaston, B15 2TT, UK
b Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA
c Department of Urology, Queen Elizabeth Hospital, Edgbaston, Birmingham, B15 2TH, UK
d Uro-Oncology Research Group, Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK

e Corresponding Author; Moray.Campbell{at}RoswellPark.org

Increasingly invasive bladder cancer cells lines displayed insensitivity towards a panel of dietary-derived ligands for members of the nuclear receptor superfamily. Insensitivity was defined through altered gene regulatory actions and cell proliferation and reflected both reduced receptor expression and elevated NCOR1 expression. Stable over-expression of NCOR1 in sensitive cells (RT4) resulted in a panel of clones that recapitulated the resistant phenotype in terms of gene regulatory actions and proliferative responses towards ligand. Similarly siRNA approaches to NCOR1 in resistant cells (EJ28) enhanced ligand gene regulatory and proliferation responses, including those mediated by PPAR{gamma} and VDR receptors. Elevated NCOR1 levels generate an epigenetic lesion to target in resistant cells using the HDAC inhibitor vorinostat, in combination with nuclear receptor ligands. Such treatments revealed strong additive interactions towards the PPAR{gamma}, VDR and FXR receptors. Genome wide micro-array and micro-fluidic Q-RT-PCRM approaches, following the targeting of NCOR1 activity and expression, revealed the selective capacity of this co-repressor to govern common transcriptional events of underlying networks. Combined these findings suggest that NCOR1 is a selective regulator of nuclear receptors, notably PPAR{gamma} and VDR, and contributes to their loss of sensitivity. Combinations of epigenetic therapies that target NCOR1 may prove effective, even when receptor expression is reduced.

Key Words: NCOR1 • bladder cancer • chemotherapy • HDACs • nuclear receptors

Received September 30, 2008; revised December 8, 2008; accepted December 26, 2008.


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