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EXTRACELLULAR MATRIX, CELL INTERACTIONS

Epigenetic regulation of integrin-linked kinase expression depending on adhesion of gastric carcinoma cells

Cancer Research Institute, Departments of ¹Tumor Biology, ²Molecular and Clinical Oncology, and ³Pharmacology, College of Medicine, Seoul National University, Seoul, Korea

Submitted 10 April 2006 ; accepted in final form 13 September 2006

Cell adhesion to the extracellular matrix (ECM) regulates gene expressions in diverse dynamic environments. However, the manner in which gene expressions are regulated by extracellular cues is largely unknown. In this study, suspended gastric carcinoma cells showed higher basal and transforming growth factor-1 (TGF1)-mediated acetylations of histone 3 (H3) and Lys⁹ of H3 and levels of integrin-linked kinase (ILK) mRNA and protein than did fibronectin-adherent cells did. Moreover, the insignificant acetylation and ILK expression in adherent cells were recovered by alterations of integrin signaling and actin organization, indicating a connection between cytoplasmic and nuclear changes. Higher acetylations in suspended cells were correlated with associations between Smad4, p300/CBP, and Lys⁹-acetylated H3. Meanwhile, adherent cells showed more associations between HDAC3, Ski, and MeCP2. Chromatin immunoprecipitations with anti-acetylated H3, Lys⁹-acetylated H3, or p300/CBP antibody resulted in more coprecipitated ILK promoter, correlated with enhanced ILK mRNA and protein levels, in suspended cells. Moreover, ILK expression inversely regulated cell adhesion to ECM proteins, and its overexpression enhanced cell growth in soft agar. These observations indicate that cell adhesion and/or its related molecular basis regulate epigenetic mechanisms leading to a loss of ILK transcription, which in turn regulates cell adhesion property in a feedback linkage.

cell adhesion; integrin-linked kinase; histone acetylation; gastric cancer