HDAC1 controls CIP2A transcription in human colorectal cancer cells

// Manjola Balliu 1 , Cristina Cellai 2 , Matteo Lulli 2 , Anna Laurenzana 2 , Eugenio Torre 2 , Alessandro Maria Vannucchi 1 , Francesco Paoletti 2 1 Department of Experimental and Clinical Medicine, University of Florence, 50134 Firenze, Italy 2 Department of Biomedical, Experimental and Clinical Sciences “Mario Serio”, 50134 Firenze, Italy Correspondence to: Manjola Balliu, e-mail: manjola.balliu@unifi.it Francesco Paoletti, e-mail: f.paoletti.fi@alice.it Keywords: HDAC-inhibitor, HDAC1, CIP2A transcription, PP2A, CRC cells Received: February 01, 2016      Accepted: March 10, 2016      Published: March 26, 2016 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.