The coupling of epidermal growth factor receptor down regulation by 1alpha,25-dihydroxyvitamin D3 to the hormone-induced cell cycle arrest at the G1-S checkpoint in ovarian cancer cells

• Published in: Molecular and cellular endocrinology 2011-05, Vol.338 (1), p.58-67
• Main Authors: Shen, Zheng, Zhang, Xiaohui, Tang, Jinfu, Kasiappan, Ravi, Jinwal, Umesh, Li, Pengfei, Hann, Shan, Nicosia, Santo V., Wu, Jie, Zhang, Xiaohong, Bai, Wenlong
• Format: Article
• Language: English
• Subjects: animal ovaries; Calcitriol - pharmacology; Cancer; Cell cycle; Cell Line, Tumor; Cell Proliferation - drug effects; chromatin; Control; Cyclin-Dependent Kinase Inhibitor p27 - metabolism; Cyclins - metabolism; DNA; Down-Regulation - drug effects; EGF; EGFR; epidermal growth factor; Epidermal Growth Factor - pharmacology; epidermal growth factor receptors; Female; G1 Phase - drug effects; gene expression; Gene Expression Regulation, Neoplastic - drug effects; Genes; Genes, Reporter; Growth factors; hormonal regulation; Human; Humans; Introns; Kinases; Luciferases, Firefly - biosynthesis; Luciferases, Firefly - genetics; messenger RNA; neoplasm cells; Ovarian cancer; ovarian neoplasms; Ovarian Neoplasms - physiopathology; precipitin tests; Receptor, Epidermal Growth Factor - agonists; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - genetics; Receptors; reporter genes; Signal Transduction; transcription (genetics); transfection; Vitamin D; Vitamin D receptor; Vitamin D Response Element; Vitamins
• ISSN: 0303-7207; 1872-8057
• DOI: 10.1016/j.mce.2011.02.023

► A novel VDRE is identified in the intron 1 of EGFR genome, a hotspot for the transcriptional control of EGFR mRNA expression. ► The VDRE binds in vivo to the VDR and a corepressor. ► The EGFR down regulation contributes to the suppression of ovarian cancer cell growth to 1,25(OH) 2D 3. ► The EGFR down regulation is linked to cell cycle arrest at G1-S checkpoint induced by 1,25(OH) 2D 3. 1alpha,25-dihydroxyvitamin D3, 1,25(OH) 2D 3, regulates gene expression through the vitamin D receptor. The present studies identify the epidermal growth factor receptor, EGFR, as a target gene suppressed by 1,25(OH) 2D 3 in human ovarian cancer cells. The suppression was detected at both mRNA and protein levels in vitamin D-sensitive human ovarian cancer cells. A novel vitamin D response element was identified in intron 1 of the EGFR genome, a known hotspot for its transcriptional regulation. Chromatin immunoprecipitations and reporter gene analyses showed that the intronic DNA element bound to vitamin D receptor and a co-repressor and was functional in mediating transcriptional suppression of EGFR promoter by 1,25(OH) 2D 3 under stable transfection conditions. Consistent with the EGFR down regulation, 1,25(OH) 2D 3 suppressed activation of the external signal regulated kinase by epidermal growth factors. Over expression of an active EGFR in vitamin D sensitive ovarian cancer cells caused resistance to 1,25(OH) 2D 3-induced growth suppression and diminished the hormonal regulation of cyclin D1, cyclin E, Skp2 and p27, a group of cell cycle regulators that mediate 1,25(OH) 2D 3-induced cell cycle arrest at G1-S checkpoint. Taken together, our studies demonstrate that 1,25(OH) 2D 3 suppresses the response of human ovarian cancer cells to mitogenic growth factors and couple the suppression to the cell cycle arrest at G1-S checkpoint by the hormone.