Interplay of transcription factors STAT3, STAT1 and AP-1 mediates activity of the matrix metallo-proteinase-1 promoter in colorectal carcinoma cells

Annekatrin Müller, Josephine Gasch, Kai Albring, Fritz Aberger, Harini Nivarthi, Manel Khemeri, Richard Moriggl,  Karl-Heinz Friedrich

Abstract:

Signal Transducers (STATs) 1 and 3 and Activator Protein 1 (AP-1) are transcription factors involved in the development of malignancy in colorectal carcinoma (CRC). Matrix Metalloproteinase 1 (MMP-1) is a protease frequently dysregulated in de-differentiated and invasive cancer cells. Its expression is influenced by STAT and AP-1 transcription factors. We studied their contributions to transcriptional regulation of MMP-1 in colorectal carcinoma (CRC) cells. Both STAT3 and AP-1 contribute individual expression-inducing and additive effects and interact with the MMP-1 promoter. DNA binding of AP-1 protein c-Jun is stimulation-independent but modulated by STAT3 and a STAT recognition DNA element. Activated STAT3 showed a suppressive effect on AP-1-mediated MMP-1 mRNA upregulation as shown by STAT3 knockdown. Surprisingly, activated STAT1 overcame STAT3-dependent repression of AP-1-driven MMP-1 expression. Moreover, combined STAT3, STAT1 and AP-1 activities evoked maximal MMP-1 mRNA levels in a synergistic manner. Our results suggest a dominant role of AP-1 in transcriptional upregulation of MMP-1 in CRC cells which is modulated by joint functions of STAT3 and STAT1. The individual and combinatorial activity of these factors is of diagnostic and prognostic interest.