title: LRH-1 drives colon cancer cell growth by repressing the expression of the CDKN1A gene in a p53-dependent manner.
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.
authors.affiliation: Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Holly B
authors.initials: HB
authors.lastname: Kramer
authors.affiliation: Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Chun-Fui
authors.initials: CF
authors.lastname: Lai
authors.affiliation: Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Hetal
authors.initials: H
authors.lastname: Patel
authors.affiliation: Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Manikandan
authors.initials: M
authors.lastname: Periyasamy
authors.affiliation: Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Meng-Lay
authors.initials: ML
authors.lastname: Lin
authors.affiliation: Institute of Molecular Medicine, Martin-Luther-University Halle-Wittenberg, Heinrich-Damerow-Str. 1, D-06120 Halle (Saale), Germany.
authors.forename: Stephan M
authors.initials: SM
authors.lastname: Feller
authors.affiliation: Division of Cancer Research, University of Dundee, Ninewells Hospital & Medical School, Dundee DD1 9SY, UK.
authors.forename: Frances V
authors.initials: FV
authors.lastname: Fuller-Pace
authors.affiliation: Division of Cancer Research, University of Dundee, Ninewells Hospital & Medical School, Dundee DD1 9SY, UK.
authors.forename: David W
authors.initials: DW
authors.lastname: Meek
authors.affiliation: Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK simak.ali@imperial.ac.uk.
authors.forename: Simak
authors.initials: S
authors.lastname: Ali
authors.affiliation: Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK l.buluwela@imperial.ac.uk.
authors.forename: Laki
authors.initials: L
authors.lastname: Buluwela
mesh_terms: D001665:Binding Sites; D049109:Cell Proliferation / Q000235:genetics*; D042002:Chromatin Assembly and Disassembly; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics* / Q000378:metabolism; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D009154:Mutation; D009928:Organ Specificity; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C082631:NR5A2 protein, human; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D016159:Tumor Suppressor Protein p53