Depletion of histone N-terminal-acetyltransferase Naa40 induces p53-independent apoptosis in colorectal cancer cells via the mitochondrial pathway
Date
2016ISSN
1360-8185Source
ApoptosisVolume
21Pages
298-311Google Scholar check
Keyword(s):
Metadata
Show full item recordAbstract
Protein N-terminal acetylation is an abundant post-translational modification in eukaryotes implicated in various fundamental cellular and biochemical processes. This modification is catalysed by evolutionarily conserved N-terminal acetyltransferases (NATs) whose deregulation has been linked to cancer development and thus, are emerging as useful diagnostic and therapeutic targets. Naa40 is a highly selective NAT that acetylates the amino-termini of histones H4 and H2A and acts as a sensor of cell growth in yeast. In the present study, we examine the role of Naa40 in cancer cell survival. We demonstrate that depletion of Naa40 in HCT116 and HT-29 colorectal cancer cells decreases cell survival by enhancing apoptosis, whereas Naa40 reduction in non-cancerous mouse embryonic fibroblasts has no effect on cell viability. Specifically, Naa40 knockdown in colon cancer cells activates the mitochondrial caspase-9-mediated apoptotic cascade. Consistent with this, we show that caspase-9 activation is required for the induced apoptosis because treatment of cells with an irreversible caspase-9 inhibitor impedes apoptosis when Naa40 is depleted. Furthermore, the effect of Naa40-depletion on cell-death is mediated through a p53-independent mechanism since p53-null HCT116 cells still undergo apoptosis upon reduction of the acetyltransferase. Altogether, these findings reveal an anti-apoptotic role for Naa40 and exhibit its potential as a therapeutic target in colorectal cancers. © The Author(s) 2015.
Collections
Cite as
Related items
Showing items related by title, author, creator and subject.
-
Article
Silencing of human polycomb target genes is associated with methylation of histone H3 Lys 27
Kirmizis, Antonis; Bartley, S. M.; Kuzmichev, A.; Margueron, R.; Reinberg, D.; Green, R.; Farnham, P. J. (2004)Polycomb group (PcG) complexes 2 and 3 are involved in transcriptional silencing. These complexes contain a histone lysine methyltransferase (HKMT) activity that targets different lysine residues on histones H1 or H3 in ...
-
Article
The Polycomb Group Protein SUZ12 regulates histone H3 lysine 9 methylation and HP1α distribution
De La Cruz, C. C.; Kirmizis, Antonis; Simon, M. D.; Isono, K. -I; Koseki, H.; Panning, B. (2007)Regulation of histone methylation is critical for proper gene expression and chromosome function. Suppressor of Zeste 12 (SUZ12) is a requisite member of the EED/EZH2 histone methyltransferase complexes, and is required ...
-
Article
Composition and histone substrates of polycomb repressive group complexes change during cellular differentiation
Kuzmichev, A.; Margueron, R.; Vaquero, A.; Preissner, T. S.; Scher, M.; Kirmizis, Antonis; Ouyang, X.; Brockdorff, N.; Abate-Shen, C.; Farnham, P.; Reinberg, D. (2005)Changes in the substrate specificities of factors that irreversibly modify the histone components of chromatin are expected to have a profound effect on gene expression through epigenetics. Ezh2 is a histone-lysine ...