LRH-1 drives colon cancer cell growth by repressing the expression of the CDKN1A gene in a p53-dependent manner

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 (Lead / Corresponding author), Laki Buluwela (Lead / Corresponding author)

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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.

    Original languageEnglish
    Pages (from-to)582-594
    Number of pages13
    JournalNucleic Acids Research
    Volume44
    Issue number2
    Early online date22 Sep 2015
    DOIs
    Publication statusPublished - 29 Jan 2016

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