HDAC inhibitors suppress the proliferation, migration and invasiveness of human head and neck squamous cell carcinoma cells via p63-mediated tight junction molecules and p21-mediated growth arrest

Abstract

In human head and neck squamous cell carci- noma (HNSCC), the invasion and metastatic properties of cancer cells are promoted by junctional adhesion molecule-A (JAM-A) and claudin-1; these are epithelial tight junction molecules regulated by histone deacetylases (HDACs) and transcription factor p63. HDAC expression is reportedly upregulated in HNSCC, and HDAC inhibitors suppress cancer cell proliferation by initiating proliferative arrest or apoptosis. However, little is known of the anti-cancer mechanisms of HDAC inhibitors in HNSCC. Thus, in the present study, the HNSCC Detroit 562 cell line and primary cultured HNSCC cells were treated with HDAC inhibitors to investigate their effects in HNSCC. Higher expression of p63, HDAC1, JAM-A and claudin-1 was observed in HNSCC tissues compared with the adjacent dysplastic regions. In Detroit 562 cells, treatment with trichostatin A (TSA), an inhibitor of HDAC1 and 6, down- regulated the expression of p63, JAM-A and claudin-1, and upregulated that of acetylated tubulin; conversely, p63 knock- down resulted in the downregulation of JAM-A and claudin-1. Collectively, inhibiting HDAC suppressed the migration and invasiveness of cancer cells. In addition, treatment with TSA suppressed cancer cell proliferation via G2/M arrest, as well as upregulating p21 and downregulating cyclin D1 expres- sion. TSA also downregulated the expression of epidermal growth factor receptor (EGFR) and phospho-ERK1/2. p63 knockdown and treatment with an EGFR inhibitor induced G1 arrest and downregulated EGFR and phospho-ERK1/2 levels, respectively. HDAC inhibition also suppressed the migration and invasiveness of primary cultured HNSCC cells. Collectively, the results of the present study indicate that HDAC inhibitors suppress the proliferation, migration and invasiveness of HNSCC by downregulating the p63-mediated tight junction molecules JAM-A and claudin-1, and inducing p63 or p21-mediated growth arrest.