Increased expression of integrin β1 subunit enhances p21WAF1/Cip1 transcription through the Sp1 sites and p300‐mediated histone acetylation in human hepatocellular carcinoma cells

Integrins, a class of membrane receptors, are major players in transmitting the mechanical force across the plasma membrane. We previously reported that overexpression of integrin β1 subunit imposed a growth inhibitory effect on the hepatocellular carcinoma cell line SMMC-7721 through transcriptional activation of p21WAF1/CIP1 gene. In this study, we further determined the molecular mechanisms underlying p21WAF1/CIP1 expression induced by integrin β1 overexpression. We report herein that overexpression of integrin β1 subunit upregulates p21WAF1/Cip1 transcription through a p53-independent pathway. The overexpressed integrin β1 activates the p21WAF1/Cip1 promoter through the Sp1/Sp3 sites and makes more transcription factor Sp1 recruited to the proximal p21 promoter region. In addition, it makes the acetylation value of histone proteins increased across some parts of the p21WAF1/Cip1 gene, especially in the promoter region. The transcriptional co-activator p300, which possesses intrinsic histone acetyltransferase, was found to be involved in the integrin β1-mediated histone acetylation and p21 transcriptional activation. Therefore, these findings presented the mechanisms by which integrin β1 induced the elevated p21 expression in hepatic cancer cells. J. Cell. Biochem. 101: 654–664, 2007. © 2007 Wiley-Liss, Inc.