LRH-1 drives colon cancer cell growth by repressing the expression of the CDKN1A gene in a p53-dependent manner |
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| Authors: | Holly B Kramer Chun-Fui Lai Hetal Patel Manikandan Periyasamy Meng-Lay Lin Stephan M Feller Frances V Fuller-Pace David W Meek Simak Ali Laki Buluwela |
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| Institution: | 1Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK;2Institute of Molecular Medicine, Martin-Luther-University Halle-Wittenberg, Heinrich-Damerow-Str. 1, D-06120 Halle (Saale), Germany;3Division of Cancer Research, University of Dundee, Ninewells Hospital & Medical School, Dundee DD1 9SY, UK |
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| Abstract: | Liver receptor homologue 1 (LRH-1) is an orphan nuclear receptor that has been implicated in the progression of breast, pancreatic and colorectal cancer (CRC). To determine mechanisms underlying growth promotion by LRH-1 in CRC, we undertook global expression profiling following siRNA-mediated LRH-1 knockdown in HCT116 cells, which require LRH-1 for growth and in HT29 cells, in which LRH-1 does not regulate growth. Interestingly, expression of the cell cycle inhibitor p21 (CDKN1A) was regulated by LRH-1 in HCT116 cells. p21 regulation was not observed in HT29 cells, where p53 is mutated. p53 dependence for the regulation of p21 by LRH-1 was confirmed by p53 knockdown with siRNA, while LRH-1-regulation of p21 was not evident in HCT116 cells where p53 had been deleted. We demonstrate that LRH-1-mediated p21 regulation in HCT116 cells does not involve altered p53 protein or phosphorylation, and we show that LRH-1 inhibits p53 recruitment to the p21 promoter, likely through a mechanism involving chromatin remodelling. Our study suggests an important role for LRH-1 in the growth of CRC cells that retain wild-type p53. |
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