p21(WAF1/Cip1) Regulation by hYSK1 Activates SP-1 Transcription Factor and Increases MMP-2 Expression under Hypoxic Conditions

The hYSK1, a serine/threonine kinase (STK)-25, has been implicated in a variety of cellular functions including cell migration and polarity. We have recently reported that hYSK1 down-regulated the expression and functions of p16(INK4a), a cell cycle regulatory protein, thereby enhancing migration and growth of cancer cells under hypoxic conditions. In this study, we further investigated the mechanisms underlying downregulation of p16(INK4a) and anti-migratory function of hYSK1. Our study revealed that p21(WAF1/Cip1) is a novel binding partner of hYSK1. Moreover, the interaction between hYSK1 and p21(WAF1/Cip1) led to the inhibition of SP-1 transcriptional activity, as revealed by a significant down-regulation of SP-1-mediated transactivation of p16(INK4a) promoter, and accelerated MMP-2 expression. Conversely, the knock-down of hYSK1 enhanced the p16(INK4a) promoter activity and protein expression, and diminished MMP-2 transcription and protein levels in hypoxic conditions as compared to control. Taken together, hYSK1 blocks the p21(WAF1/Cip1) functions by direct interaction and inhibits the p16(INK4a) expression and induces MMP-2 expression by its regulations of SP-1 transcriptional activity under the hypoxia conditions.