title: Keratin 23 (K23), a novel acidic keratin, is highly induced by histone deacetylase inhibitors during differentiation of pancreatic cancer cells.
abstract: Sodium butyrate (NaBu) was shown to induce differentiation and apoptosis in the human pancreatic cancer cell line AsPC-1. A suppression subtractive hybridization-based technique was used to identify genes induced by NaBu. A novel cDNA was found to be highly up-regulated in AsPC-1 cells in response to NaBu. The gene expresses a 1.65-kb mRNA encoding a protein with an open reading frame of 422 amino acids. It has an intermediate filament signature sequence and extensive homology to type I keratins. Sequence comparison with known keratins indicated that the gene shares 42-46% amino acid identity and 60-65% similarity within the alpha-helical rod domain. The gene is named K23 (for human type I Keratin 23, KRT23). K23 mRNA was highly induced by NaBu in different pancreatic cancer cells. Trichostatin A (TSA), a potent and specific inhibitor of histone deacetylase, similarly induced K23 mRNA expression. Treatment with either actinomycin D or cycloheximide efficiently blocked 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 hyperacetylation. 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 induced in pancreatic cancer cells undergoing differentiation by a mechanism involving histone hyperacetylation. p21(WAF1/CIP1) serves as an important mediator during the induction process of K23 by NaBu.
authors.affiliation: Division of Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Foundation, Rochester, Minnesota 55905, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Zhang
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.forename: H
authors.initials: H
authors.lastname: Huang
authors.forename: M
authors.initials: M
authors.lastname: Nelson
authors.forename: D I
authors.initials: DI
authors.lastname: Smith
mesh_terms: D000107:Acetylation; D000595:Amino Acid Sequence; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001483:Base Sequence; D002087:Butyrates / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D003001:Cloning, Molecular; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D007381:Intermediate Filament Proteins / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification; D007633:Keratins / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics; D053530:Keratins, Type I; D008969:Molecular Sequence Data; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000096:biosynthesis; D017386:Sequence Homology, Amino Acid; D014407:Tumor Cells, Cultured
chemical_list: D002087:Butyrates; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D007381:Intermediate Filament Proteins; C420247:KRT23 protein, human; D053530:Keratins, Type I; D012333:RNA, Messenger; D007633:Keratins; D006655:Histone Deacetylases