title: Depletion of histone N-terminal-acetyltransferase Naa40 induces p53-independent apoptosis in colorectal cancer cells via the mitochondrial pathway.
abstract: 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.
authors.affiliation: Department of Biological Sciences, University of Cyprus, Nicosia, Cyprus.
authors.forename: Demetria
authors.initials: D
authors.lastname: Pavlou
authors.affiliation: Department of Biological Sciences, University of Cyprus, Nicosia, Cyprus. kirmizis@ucy.ac.cy.
authors.forename: Antonis
authors.initials: A
authors.lastname: Kirmizis
mesh_terms: D000107:Acetylation; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D063646:Carcinogenesis / Q000235:genetics*; D053453:Caspase 9 / Q000378:metabolism*; D061945:Caspase Inhibitors / Q000494:pharmacology; D002470:Cell Survival; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D019073:HT29 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D063212:N-Terminal Acetyltransferase D / Q000235:genetics / Q000502:physiology*; D011499:Protein Processing, Post-Translational / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D061945:Caspase Inhibitors; D006657:Histones; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D063212:N-Terminal Acetyltransferase D; C523773:NAA40 protein, human; C506433:CASP9 protein, human; D053453:Caspase 9
keywords: Apoptosis; Colorectal cancer; Epigenetics; Histone N-terminal acetylation; Naa40; NatD