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J. Biol. Chem., Vol. 282, Issue 32, 23387-23401, August 10, 2007

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Functional Genomic Analysis Reveals Cross-talk between Peroxisome Proliferator-activated Receptor and Calcium Signaling in Human Colorectal Cancer Cells^*

Craig R. Bush¹, Jennifer M. Havens, Brian M. Necela, Weidong Su, Lu Chen^¶, Masahiro Yanagisawa, Panos Z. Anastasiadis², Rudy Guerra^||, Bruce A. Luxon^**, and E. Aubrey Thompson³

From the Cancer Genomics Center, Texas Children's Hospital, Houston, Texas 77030, the Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, Florida 32224, ^¶Baylor College of Medicine, Breast Center, Houston, Texas 77030, ^||Department of Statistics, Rice University, Houston, Texas 77251, and ^**Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas 77555

Activation of PPAR in MOSER cells inhibits anchorage-dependent and anchorage-independent growth and invasion through Matrigel-coated transwell membranes. We carried out a longitudinal two-class microarray analysis in which mRNA abundance was measured as a function of time in cells treated with a thiazolidinedione PPAR agonist or vehicle. A statistical machine learning algorithm that employs an empirical Bayesian implementation of the multivariate HotellingT2 score was used to identify differentially regulated genes. HotellingT2 scores, MB statistics, and maximum median differences were used as figures of merit to interrogate genomic ontology of these targets. Three major cohorts of genes were regulated: those involved in metabolism, DNA replication, and migration/motility, reflecting the cellular phenotype that attends activation of PPAR. The bioinformatic analysis also inferred that PPAR regulates calcium signaling. This response was unanticipated, because calcium signaling has not previously been associated with PPAR activation. Ingenuity pathway analysis inferred that the nodal point in this cross-talk was Down syndrome critical region 1 (DSCR1). DSCR1 is an endogenous calcineurin inhibitor that blocks dephosphorylation and activation of members of the cytoplasmic component of nuclear factor of activated T cells transcription factors. Lentiviral short hairpin RNA-mediated knockdown of DSCR1 blocks PPAR inhibition of proliferation and invasion, indicating that DSCR1 is required for suppression of transformed properties of early stage colorectal cancer cells by PPAR. These data reveal a novel, heretofore unappreciated link between PPAR and calcium signaling and indicate that DSCR1, which has previously been thought to function by suppression of the angiogenic response in endothelial cells, may also play a direct role in transformation of epithelial cells.

Received for publication, March 29, 2007 , and in revised form, June 11, 2007.

^* This work was supported in part by grants from Sankyo Co., Ltd. (to E. A. T.), NCI Grants CA121349 and CA127996 from the National Institutes of Health, and from the University of Texas Medical Branch Bioinformatics Program Tobacco Funds. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental text, Figs. S1–S6, Tables SI–SIV, and Refs. 1–9.

¹ Supported by a training fellowship from the Keck Center for Computational and Structural Biology of the Gulf Coast Consortia NLM Grant 5 T15-LM07093.

² Supported by NCI Grant CA100467 from the National Institutes of Health.

³ To whom correspondence should be addressed: Dept. of Cancer Biology, Griffin Cancer Research Bldg., Rm. 304, Mayo Clinic Comprehensive Cancer Center, 4500 San Pablo Rd., Jacksonville, FL 32224. Tel.: 904-953-6226; E-mail: Thompson.aubrey{at}mayo.edu.

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