Oncotarget

Research Papers:

HDAC1 controls CIP2A transcription in human colorectal cancer cells

Manjola Balliu _, Cristina Cellai, Matteo Lulli, Anna Laurenzana, Eugenio Torre, Alessandro Maria Vannucchi and Francesco Paoletti

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Oncotarget. 2016; 7:25862-25871. https://doi.org/10.18632/oncotarget.8406

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Abstract

Manjola Balliu1, Cristina Cellai2, Matteo Lulli2, Anna Laurenzana2, Eugenio Torre2, Alessandro Maria Vannucchi1, Francesco Paoletti2

1Department of Experimental and Clinical Medicine, University of Florence, 50134 Firenze, Italy

2Department of Biomedical, Experimental and Clinical Sciences “Mario Serio”, 50134 Firenze, Italy

Correspondence to:

Manjola Balliu, e-mail: [email protected]

Francesco Paoletti, e-mail: [email protected]

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.


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