LXRα-mediated downregulation of FOXM1 suppresses the proliferation of hepatocellular carcinoma cells

Abstract

Liver X receptors (LXRs), including LXRα and LXRβ isoforms, have important roles in the metabolic regulation of glucose, cholesterol and lipid. Moreover, activation of LXRs also represses the expression of cyclin D1 and cyclin B1, and thus suppresses the proliferation of multiple cancer cells, but the relevant mechanism is not well known. Forkhead box M1 (FOXM1) is a proliferation-specific member of forkhead box family, which is highly expressed in proliferating normal cells and numerous cancer cells. FOXM1 directly activates transcription of cyclin D1 and cyclin B1, resulting in the enhancement of cell cycle progression and cell proliferation. However, it is unclear whether LXRs are involved in the regulation of FOXM1. In this study, we demonstrated that specific LXRs agonists downregulated expression of FOXM1, cyclin D1 and cyclin B1 in hepatocellular carcinoma (HCC) cells, which led to cell cycle and cell proliferation arrest. Knockdown of FOXM1 significantly alleviated LXRs activation-mediated cell cycle arrest and cell growth suppression. Reporter assays showed that the activation of LXRs significantly reduced the transcriptional activity of FOXM1 promoter. Electrophoretic mobility shift assay and chromatin immunoprecipitation assays demonstrated that LXRα but not LXRβ could bind to an inverted repeat IR2 (-52CCGTCAcgTGACCT-39) in the promoter region of FOXM1 gene. Moreover, the xenograft tumor growth and the corresponding FOXM1 expression in nude mice were dramatically repressed by LXRs agonists. Taken together, we conclude that LXRα but not LXRβ functions as a transcriptional repressor for FOXM1 expression. The pathway 'LXRα-FOXM1-cyclin D1/cyclin B1' is a novel mechanism by which LXRs suppress the proliferation of HCC cells, suggesting that the pathway may be a novel target for HCC treatment.

hTERT promotes the invasion of gastric cancer cells by enhancing FOXO3a ubiquitination and subsequent ITGB1 upregulation

“…After the protein concentrations were measured with a Bradford Protein Assay Kit (Biyuntian, Beijing, China), western blot analysis was performed as previously described 12. The antibodies against NDRG1, ITGB1, PRAF2, SIRT1, S100A9, ATOX1, CD97, KDR, VASP, SMURF1, FOXM1, FOXO3a, SP1 and GAPDH were obtained from Abcam (Cambridge, Massachusetts, USA), and the antibodies against MDM2 and β-TRCP were obtained from Santa Cruz (Santa Cruz, California, USA).…”

Hepatocyte growth factor (HGF) upregulates heparanase expression via the PI3K/Akt/NF-κB signaling pathway for gastric cancer metastasis

“…[30] Approximately 5 µg anti-p65 and rabbit anti-IgG antibodies were used for immunoprecipitation, and immunoprecipitate complexes were collected with Dynal magnetic beads (Invitrogen). The primers used in the ChIP assay were as follow: BS1: …”

FOXM1 regulates glycolysis in hepatocellular carcinoma by transactivating glucose transporter 1 expression

“…The aberrant expression of FOXM1 is involved in cancer proliferation (16,17), epithelialmesenchymal transition, metastasis (10) and stem cell features (18) in hepatocellular carcinoma (HCC). However, the significance of FOXM1 in HCC glycolysis has not been established.…”