Cell adhesion status-dependent histone acetylation is regulated through intracellular contractility-related signaling activities.

Although histone acetylation is important for epigenetic gene transcription, histone acetylation regulation by extracellular cues has rarely been evidenced. Here, we examined whether and how histone acetylation is regulated by cell adhesion-mediated signaling. Gastric carcinoma cells in suspension showed a higher histone acetylation, compared with fibronectin-adherent cells. This difference was supported by a decreased histone deacetylases activity. Furthermore, trichostatin A (TSA)-mediated histone acetylation was significantly increased only in suspended, but not in fibronectin-adherent, cells. Pharmacological inhibition of intracellular contractility-related myosin light chain kinase or RhoA-kinase (ROCK) or expression of ROCK1 small interfering RNA, dominant negative RhoA, or active Rac1 decreased basal and TSA-mediated histone H3 acetylations in suspended cells,whereas inhibition of calmodulin-dependent protein kinase II or transient overexpression of wild type myosin light chain kinase enhanced the acetylations. Meanwhile, chromatin immunoprecipitation showed higher basal and TSA-enhanced associations of ROCK1 promoter regions with Lys(9)-acetylated histone 3 in suspended cells than in fibronectin-adherent cells and expression of ROCK1 was higher and further increased by TSA treatment in suspension. In addition, phosphorylation of myosin light chain was further increased by TSA in suspension and higher in anchorage-independent cells over adherently growing cells, indicating an inverse relationship between ROCK1 expression-mediated contractility and cell adhesion abilities. Cell adhesion analysis showed that pharmacological activation of intracellular contractility-related signaling activities decreased cell adhesion abilities, whereas inhibition of them increased the adhesion. Taken together, these observations suggest that cell adhesion-related signal transduction regulates histone acetylation, presumably through a close functional linkage between intracellular contractility and histone deacetylases activity/histone acetylation.