Increased expression of integrin beta1 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 beta1 subunit imposed a growth inhibitory effect on the hepatocellular carcinoma cell line SMMC-7721 through transcriptional activation of p21(WAF1/CIP1) gene. In this study, we further determined the molecular mechanisms underlying p21(WAF1/CIP1) expression induced by integrin beta1 overexpression. We report herein that overexpression of integrin beta1 subunit upregulates p21(WAF1/Cip1) transcription through a p53-independent pathway. The overexpressed integrin beta1 activates the p21(WAF1/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 p21(WAF1/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 beta1-mediated histone acetylation and p21 transcriptional activation. Therefore, these findings presented the mechanisms by which integrin beta1 induced the elevated p21 expression in hepatic cancer cells.
Fang
Zhengyu
Z
Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, 138 Yi Xue Yuan Road, Shanghai 200032, PR China.
Fu
Yi
Y
Liang
Yulong
Y
Li
Zengxia
Z
Zhang
Wen
W
Jin
Jiawei
J
Yang
Yong
Y
Zha
Xiliang
X
D000107:Acetylation; D001665:Binding Sites; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000378:metabolism*; D006801:Humans; D019012:Integrin beta1 / Q000235:genetics* / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010957:Plasmids / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D051705:Sp3 Transcription Factor / Q000378:metabolism; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000378:metabolism*
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D006657:Histones; D019012:Integrin beta1; D016329:Sp1 Transcription Factor; D016159:Tumor Suppressor Protein p53; D051705:Sp3 Transcription Factor; D050880:p300-CBP Transcription Factors