Plau codes for the urokinase-type plasminogen activator (uPA), critical in cancer metastasis. While the mechanisms driving its overexpression in tumorigenic processes are unknown, it is regulated by the AP-1 transcriptional complex in diverse situations. The AP-1 component Fra-1 being overexpressed in aggressive breast cancers, we have addressed its role in the overexpression of Plau in the highly metastatic breast cancer model cell line MDA-MB231 using ChIP, pharmacological and RNAi approaches. Plau transcription appears controlled by 2 AP-1 enhancers located -1.9 (ABR-1.9) and -4.1 kb (ABR-4.1) upstream of the transcription start site (TSS) of the uPA-coding mRNA, Plau-001, that bind Fra-1. Surprisingly, RNA Pol II is not recruited only at the Plau-001 TSS but also upstream in the ABR-1.9 and ABR-4.1 region. Most Pol II molecules transcribe short and unstable RNAs while tracking down toward the TSS, where there are converted into Plau-001 mRNA-productive species. Moreover, a minority of Pol II molecules transcribes a low abundance mRNA of unknown function called Plau-004 from the ABR-1.9 domain, whose expression is tempered by Fra-1. Thus, we unveil a heretofore-unsuspected transcriptional complexity at Plau in a reference metastatic breast cancer cell line with pleiotropic effects for Fra-1, providing novel information on AP-1 transcriptional action.
Transcriptional complexity and roles of Fra-1/AP-1 at the uPA/Plau locus in aggressive breast cancer
Moquet-Torcy, G.; Tolza, C.; Piechaczyk, M.; Jariel-Encontre, I.
Nucleic Acids Res
2014 / vol 42 / pages 11011-24
10.1093/nar/gku814 gku814 [pii]
1362-4962 (Electronic) 0305-1048 (Linking)
Cell Line, Tumor; Female; Humans; *Transcription, Genetic; Genetic Loci; Promoter Regions, Genetic; *Gene Expression Regulation, Neoplastic; Breast Neoplasms/*genetics/metabolism/pathology; Chromatin/chemistry; Neoplasm Metastasis; Proto-Oncogene Proteins c-fos/metabolism/*physiology; Transcription Factor AP-1/*physiology; Urokinase-Type Plasminogen Activator/*genetics/metabolism