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.
Highlights
Epigenetic changes are reversible rearrangements of chromatin capable of modulating gene expression in the cell without altering DNA sequence
Among the multifaceted drug-induced events described 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 colorectal cancer (CRC)
The drug-mediated decrease of CIP2A expression in HCT116 cells has clearly indicated that histone deacetylases (HDACs) were involved in the regulation of this particular gene; and, we evaluated the effects of specific siRNAs towards the nuclear histone deacetylase HDAC1 that we previously reported to be a sensitive target of (S)-2 [21]
Summary
Epigenetic changes are reversible rearrangements of chromatin capable of modulating gene expression in the cell without altering DNA sequence. HDACis have proven effective in promoting cell cycle arrest and apoptosis in various types of tumours through the generation of reactive oxygen species, activation of caspase cascade, disruption of mitochondrial integrity, increase in autophagy [10], and suppression of pro-survival pathways [14, 15] These events were at least in part mediated by acetylation of histones and nonhistone key regulatory proteins [16] including p53, GATA1, GATA2, retinoic acid receptor, NF-kB and cytoskeletal proteins like a-tubulin [17,18,19]. Our results point to a crucial involvement of serine/threonine phosphatases and, in particular, of their physiological inhibitors, as mediators of anticancer properties of (S)-2 in CRC cells These findings disclose a new role for HDAC1 in governing transcription of the oncogenic Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A) that is known to be overexpressed in numerous cancers [23, 24] including CRCs [25]. To our knowledge, such a molecular link between HDAC1 and CIP2A has not been reported previously and may help, to understand the widespread anticancer effectiveness of several HDACis, including (S)-2, that recognize HDAC1 as a specific target
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