Differential regulation of CXC ligand 1 transcription in melanoma cell lines by poly(ADP-ribose) polymerase-1

The continuous production of the CXC ligand 1 ( CXCL1) chemokine by melanoma cells is a major effector of tumor growth. We have previously shown that the constitutive expression of this chemokine is dependent upon transcription factors nuclear factor- kappa B ( NF- kappa B), stimulating protein-1 (SP1), high- mobility group-I/Y ( HMGI/Y), CAAT displacement protein ( CDP) and poly( ADPribose) polymerase- 1 ( PARP-1). In this study, we demonstrate for the first time the mechanism of transcriptional regulation of CXCL1 through PARP-1 in melanoma cells. In its inactive state, PARP- 1 binds to the CXCL1 promoter in a sequence-specific manner and prevents binding of NF- kappa B ( p65/ p50) to its element. However, activation of the PARP- 1 enzymatic activity enhances CXCL1 expression, owing to the loss of PARP1 binding to the CXCL1 promoter, accompanied by enhanced binding of p65 to the promoter. The delineation of the role of NF-kappa B- interacting factors in the putative CXCL1 enhanceosome will provide key information in developing strategies to block constitutive expression of this and other chemokines in cancer and to develop targeted therapy.