Depletion of histone N-terminal-acetyltransferase Naa40 induces p53-independent apoptosis in colorectal cancer cells via the mitochondrial pathway

Apoptosis. 2016 Mar;21(3):298-311. doi: 10.1007/s10495-015-1207-0.

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.

Keywords: Apoptosis; Colorectal cancer; Epigenetics; Histone N-terminal acetylation; Naa40; NatD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • Apoptosis / genetics*
  • Carcinogenesis / genetics*
  • Caspase 9 / metabolism*
  • Caspase Inhibitors / pharmacology
  • Cell Survival
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology
  • Gene Knockdown Techniques
  • HCT116 Cells
  • HT29 Cells
  • Histones / metabolism
  • Humans
  • Mice
  • Mitochondria / metabolism*
  • N-Terminal Acetyltransferase D / genetics
  • N-Terminal Acetyltransferase D / physiology*
  • Protein Processing, Post-Translational / genetics
  • RNA, Small Interfering / genetics
  • Signal Transduction
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Caspase Inhibitors
  • Histones
  • RNA, Small Interfering
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • N-Terminal Acetyltransferase D
  • NAA40 protein, human
  • CASP9 protein, human
  • Caspase 9