title: HDAC1 controls CIP2A transcription in human colorectal cancer cells.
abstract: This work describes the effectiveness of HDAC-inhibitor (S)-2 towards colorectal cancer (CRC) HCT116 cells in vitro by inducing cell cycle arrest and apoptosis, and in vivo by contrasting tumour growth in mice xenografts. Among the multifaceted drug-induced events described herein, an interesting link has emerged between the oncoprotein histone deacetylase HDAC1 and the oncogenic Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A) which is overexpressed in several cancers including CRCs. HDAC1 inhibition by (S)-2 or specific siRNAs downregulates CIP2A transcription in three different CRC cell lines, thus restoring the oncosuppressor phosphatase PP2A activity that is reduced in most cancers. Once re-activated, PP2A dephosphorylates pGSK-3β(ser9) which phosphorylates β-catenin that remains within the cytosol where it undergoes degradation. The decreased amount/activity of β-catenin transcription factor prompts cell growth arrest by diminishing c-Myc and cyclin D1 expression and abrogating the prosurvival Wnt/β-catenin signaling pathway. These results are the first evidence that the inhibition of HDAC1 by (S)-2 downregulates CIP2A transcription and unleashes PP2A activity, thus inducing growth arrest and apoptosis in CRC cells.
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, 50134 Firenze, Italy.
authors.forename: Manjola
authors.initials: M
authors.lastname: Balliu
authors.affiliation: Department of Biomedical, Experimental and Clinical Sciences "Mario Serio", 50134 Firenze, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Cellai
authors.affiliation: Department of Biomedical, Experimental and Clinical Sciences "Mario Serio", 50134 Firenze, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Lulli
authors.affiliation: Department of Biomedical, Experimental and Clinical Sciences "Mario Serio", 50134 Firenze, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Laurenzana
authors.affiliation: Department of Biomedical, Experimental and Clinical Sciences "Mario Serio", 50134 Firenze, Italy.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Torre
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, 50134 Firenze, Italy.
authors.forename: Alessandro Maria
authors.initials: AM
authors.lastname: Vannucchi
authors.affiliation: Department of Biomedical, Experimental and Clinical Sciences "Mario Serio", 50134 Firenze, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Paoletti
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001324:Autoantigens / Q000096:biosynthesis*; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D045325:HCT116 Cells; D064593:Heterografts; D056284:Histone Deacetylase 1 / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000096:biosynthesis*; D051379:Mice; D054648:Protein Phosphatase 2 / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D001324:Autoantigens; C500266:CIP2A protein, human; D056572:Histone Deacetylase Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D054648:Protein Phosphatase 2; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1
keywords: CIP2A transcription; CRC cells; HDAC-inhibitor; HDAC1; PP2A