title: p21Waf1/Cip1 is a common target induced by short-chain fatty acid HDAC inhibitors (valproic acid, tributyrin and sodium butyrate) in neuroblastoma cells.
abstract: Histone acetyltransferase and histone deacetylase (HDAC) determine the acetylation status of histones, and thereby control the regulation of gene expression. HDAC inhibitors have been found to inhibit the growth of a variety of tumor cells in vitro and in vivo. We demonstrated previously that the short-chain fatty acid compound butyrate and its derivative tributyrin (both HDAC inhibitors) arrest cell growth and induce differentiation in human neuroblastoma (NB) cells. In the current study we investigated the effect of the HDAC inhibitor valproic acid (VPA) on proliferation and differentiation in human NB cells (SJ-N-KP, AF8). Treatment with VPA resulted in a strong inhibition of cell proliferation and induction of cell differentiation, as revealed by neurite outgrowth and increase of acetylcholinesterase specific activity. Moreover, we addressed the question of whether the cyclin-dependent kinase inhibitors p21(Cip1) and p27(Kip1) are involved in the mechanism of action of members of the short-chain fatty acids class (VPA, sodium butyrate and tributyrin) of HDAC inhibitors, in human NB cells. We demonstrated that p21(Cip1) is a common target of induction of transcription and protein expression for all the three compounds, while only VPA induced a concomitant increase of p27(Kip1) gene expression. These results suggest that p21(Cip1) could be involved in the inhibition of proliferation and induction of differentiation in human NB cells induced by treatment with VPA or tributyrin or sodium butyrate. Moreover, p21(Cip1) could be applied in the molecular monitoring of drug action in the possible therapeutic application of these short-chain fatty acid members of HDAC inhibitors for human NB treatment.
authors.affiliation: Department of Experimental Pathology, University of Bologna, Bologna, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Rocchi
authors.forename: Roberto
authors.initials: R
authors.lastname: Tonelli
authors.forename: Consuelo
authors.initials: C
authors.lastname: Camerin
authors.forename: Stefania
authors.initials: S
authors.lastname: Purgato
authors.forename: Raffaele
authors.initials: R
authors.lastname: Fronza
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Bianucci
authors.forename: Francesco
authors.initials: F
authors.lastname: Guerra
authors.forename: Andrea
authors.initials: A
authors.lastname: Pession
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Ferreri
mesh_terms: D000107:Acetylation; D000110:Acetylcholinesterase / Q000378:metabolism; D002087:Butyrates / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005227:Fatty Acids / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D016501:Neurites / Q000187:drug effects / Q000378:metabolism; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014280:Triglycerides / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014635:Valproic Acid / Q000494:pharmacology
chemical_list: D002087:Butyrates; C493956:CDKN1A protein, human; C436291:CDKN1B protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D056572:Histone Deacetylase Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D014280:Triglycerides; D050760:Cyclin-Dependent Kinase Inhibitor p27; D014635:Valproic Acid; D000110:Acetylcholinesterase; D006655:Histone Deacetylases; C005830:tributyrin