Keratin 23 (K23), a novel acidic keratin, is highly induced by histone deacetylase inhibitors during differentiation of pancreatic cancer cells

Sodium butyrate (NaBu) was shown to induce differentiation and apoptosis in the human pancreatic cancer cell line AsPC-I. A suppression subtractive hy bridization-based technique was used to identify genes induced by NaBu. A n ovel cDNA was found to be highly up-regulated in AsPC-I cells in response t o NaBu. The gene expresses a 1.65-kb mRNA encoding a protein with an open r eading frame of 422 amino acids. It has an intermediate filament signature sequence and extensive homology to type I keratins. Sequence comparison wit h known keratins indicated that the gene shares 42-46% amino acid identity and 60-65% similarity within the ct-helical rod domain. The gene is named K 23 (for human type I Keratin 23, KRT23). K23 mRNA was highly induced by NaB u in different pancreatic cancer cells. Trichostatin A (TSA), a potent and specific inhibitor of histone deacetylase, similarly induced K23 mRNA expre ssion. Treatment with either actinomycin D or cycloheximide efficiently blo cked the induction of K23 mRNA by NaBu/TSA. These results indicate that K23 mRNA induction by NaBu or TSA is a downstream event of histone hyperacetyl ation. We also demonstrated that expression of p21(WAF1/CIP1) antisense RNA efficiently blocked the induction of K23 mRNA induced by NaBu. Our results suggest that K23 is a novel member of the acidic keratin family that is in duced in pancreatic cancer cells undergoing differentiation by a mechanism involving histone hyperacetylation. p21(WAF1/CIP1) serves as an important m ediator during the induction process of K23 by NaBu. (C) 2001 Wiley-Liss, I nc.