HDAC1 controls CIP2A transcription in human colorectal cancer cells
| Autor: | Eugenio Torre, Matteo Lulli, Alessandro M. Vannucchi, Francesco Paoletti, Cristina Cellai, Anna Laurenzana, Manjola Balliu |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
CRC cells
0301 basic medicine CIP2A transcription HDAC-inhibitor HDAC1 PP2A Cell cycle checkpoint Transcription Genetic Apoptosis Histone Deacetylase 1 Autoantigens Mice 03 medical and health sciences 0302 clinical medicine Cyclin D1 Animals Humans Medicine Protein Phosphatase 2 Transcription factor Cell Proliferation business.industry Cell growth Intracellular Signaling Peptides and Proteins Wnt signaling pathway Membrane Proteins Protein phosphatase 2 HCT116 Cells Gene Expression Regulation Neoplastic Histone Deacetylase Inhibitors 030104 developmental biology Oncology 030220 oncology & carcinogenesis Immunology Cancer research Heterografts Histone deacetylase Colorectal Neoplasms business Research Paper |
| Zdroj: | Oncotarget |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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