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-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.
Zhang
J S
JS
Division of Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Foundation, Rochester, Minnesota 55905, USA.
Wang
L
L
Huang
H
H
Nelson
M
M
Smith
D I
DI
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
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