Epigenetic regulation at the tip of the histone tails

Chromatin-associated processes, such as those involving histone modifications, play a fundamental role in the control of gene expression.

Deregulation of histone modifying enzymes and their associated marks has been implicated in the development of diseases like cancer and, therefore, understanding their biological function and role in carcinogenesis could offer new opportunities for therapeutic interventions.

Accordingly, we have focused part of our efforts on deciphering the cellular role of histone N-alpha-terminal (Nt) acetylation, a highly conserved and abundant modification whose function remained unexplored for many years because it was thought to be inert. We have initially shown in budding yeast that Nt-acetylation of histone H4, catalysed by the N-terminal acetyltransferase NAA40, controls gene expression and modulates cellular lifespan.

Considering the impact of this epigenetic mark on yeast cell growth, we are currently interested to investigate the function of human NAA40 and its mediated Nt-acetylation on histones H4 and H2A in cancer cells.

We find that NAA40 is frequently upregulated in primary human colorectal cancer (CRC) samples and depletion of NAA40 and its accompanied reduction in histone H4 Nt-acetylation diminish CRC cell growth in vitro and in vivo. Notably, NAA40 and Nt-acetylation contribute to colon cancer growth through an interplay with PRMT5-mediated histone arginine methylation to regulate the expression of essential cancer-associated genes. More recently, transcriptome analysis unveiled a novel link between NAA40 and metabolic regulation.

Overall, our findings thus far propose that NAA40 and its associated histone Nt-acetylation are crucial epigenetic modulators in tumourigenesis and implicate these factors in rewiring cancer cell metabolism.