LRH-1 drives colon cancer cell growth by repressing the expression of theCDKN1Agene 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.

The characterization of an intestine-like genomic signature maintained during Barrett’s-associated adenocarcinogenesis reveals an NR5A2-mediated promotion of cancer cell survival

“…However, recent evidence has demonstrated important roles for NR5A2 in colon and pancreatic cancer postulated to be through hedgehog and Wnt/β-catenin signalling pathways60616263. In our study suppression of NR5A2 function by siRNA-mediated silencing or use of the CPD-3 antagonist, both resulted in significant growth arrest and detectable caspase3-mediated cleavage in OAC cells.…”

LRH1 as a promising prognostic biomarker and predictor of metastasis in patients with non‐small cell lung cancer

“…LRH1 expression is also regarded as a driving factor in pancreatic tumor growth by stimulating cyclin D1, cyclin E1, or c‐Myc . Additionally, LRH1 significantly prompts colon cancer progression by inhibiting CDKN1A expression in a p53‐dependent condition . There is an association between LRH1 and β‐catenin, which subsequently induces intestinal cell proliferation and tumorigenesis in colon cancer .…”

MERIT: Systematic Analysis and Characterization of Mutational Effect on RNA Interactome Topology

“…Identifying somatic mutation‐altered RBP–gene interactions also revealed some critical cancer‐related genes. For instance, as an inhibitor of cellular proliferation in response to DNA damage, CDKN1A had been demonstrated to play key roles in cancer . Here, we identified two mutations in the CDKN1A gene (M1R/I and D149H) that were likely to reduce the inhibition of the corresponding RBP PRPF8 (Fig.…”