Identification of an histone H3 acetylated/K4-methylated-bound intragenic enhancer regulatory for urokinase receptor expression

• Verfasst von: Wang, H. [VerfasserIn]
• Verfasst von: Yan, C. [VerfasserIn]
• Verfasst von: Asangani, Irfan A. [VerfasserIn]
• Verfasst von: Allgayer, Heike [VerfasserIn]
• Verfasst von: Boyd, D. D. [VerfasserIn]
• Titel: Identification of an histone H3 acetylated/K4-methylated-bound intragenic enhancer regulatory for urokinase receptor expression
• Verf.angabe: H. Wang, C. Yan, I. Asangani, H. Allgayer and D.D. Boyd
• Jahr: 2007
• Umfang: 13 S.
• Fussnoten: Published online 25 September 2006 ; Gesehen am 02.05.2022
• Titel Quelle: Enthalten in: Oncogene
• Ort Quelle: London : Springer Nature, 1997
• Jahr Quelle: 2007
• Band/Heft Quelle: 26(2007), 14, Seite 2058-2070
• ISSN Quelle: 1476-5594
• DOI: doi:10.1038/sj.onc.1210003
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Apoptosis
• Sach-SW: Cell Biology
• Sach-SW: general
• Sach-SW: Human Genetics
• Sach-SW: Internal Medicine
• Sach-SW: Medicine/Public Health
• Sach-SW: Oncology
• K10plus-PPN: 1800616945

Abstract

The transcriptionally regulated urokinase-type plasminogen activator receptor (u-PAR) contributes to cancer progression. Although previous studies have identified multiple 5′ regulatory elements, these cis motifs cannot fully account for u-PAR expression prompting a search for hitherto uncharacterized regulatory elements. DNase I hypersensitivity and chromatin immunoprecipitation assays using u-PAR-expressing colon cancer cells indicated a hypersensitive region (+665/+2068) in intron 1 enriched with acetylated histone 3 (H3) and H3 methylated at lysine 4, markers of regulatory regions. The +665/+2068 region increased transcription from a u-PAR-promoter in an orientation- and distance-independent manner fulfilling the criteria of an enhancer. Optimal stimulation of the u-PAR promoter by phorbol ester required this enhancer. Systematic truncations combined with DNase I footprinting revealed two protected regions (+1060/+1099 and +1123/+1134) with deletion of the latter practically abolishing enhancer activity. The +1123/+1134 region harbored non-consensus activator protein-1 and Ets1 binding sites bound with c-Jun (and/or the related JunD/JunB) and c-Fos (and/or the related FosB/Fra-1/Fra-2) as revealed with chromatin immunoprecipitation. Further, nuclear extract from resected colon cancers showed elevated protein binding to a +1123/+1134-spanning probe coordinate with elevated u-PAR protein. Thus, we have defined a novel intragenic enhancer in the u-PAR gene required for constitutive and inducible expression.