CROSSTALK OF THE TGF-?? INDUCIBLE TUMOR SUPPRESSOR KLF11 WITH OTHER TGB-??-LIKE PATHWAYS AND INVOLVEMENT WITH EXTRACELLULAR MATRIX DEPOSITION AND CELL ADHESION

Abstract

KLF11/TIEG2 was isolated by our group in 1998 as a TGF-β inducible transcription factor that acts as a tumor suppressor for pancreatic cancer via the co-repressor Sin3a-histone deacetylase complex (HDAC). Recent reports indicate that this gene correlates with either the development or aggressiveness of additional malignancies including head and neck, leukemia, and esophageal cancer. The involvement of KLF11 in the TGF-β pathway is important since this it is not only one of the most well characterized tumor suppressor pathway but also induces epithelial-to-mesenchymal transition (EMT) which involves the upregulation of extracellular matrix proteins, cell adhesion, angiogenic, and pro-metastatic molecules. However the mechanism how both TGF-β itself and KLF11 participate in these pleotrophic functions remains unknown. To address these questions, we have performed array experiments with PCR validation in combination with chromatin immunoprecipitation assays (CHIP) and promoter studies to define potential novel pathways, which can explain these phenomena. Our results reveal the existence of a crosstalk between the TGF-β/KLF11 pathways and other TGF-β-like cascades such as several members of the BMP pathway, another important tumor suppressor cascade and a regulator of mesenchymal biology. In addition, consistent with the role of TGF-β in EMT, we observed that KLF11 modulates the levels of several collagens, integrins, and TIMs. Therefore, this is the first evidence that the tumor suppressor KLF11 can target genes that may be involved in other cancer-related processes, besides the regulation of cell growth, and suggests its possible involvement in EMT and important the late TGF-β mediated tumor promoter response.