NAA40 contributes to colorectal cancer growth by controlling PRMT5 expression

Christina Demetriadou,Panagiotis Papageorgis,Apostolos Zaravinos,Antonis Kirmizis,Fotios Mpekris,Charis Achilleos,Triantafyllos Stylianopoulos,Demetria Pavlou

doi:10.1038/s41419-019-1487-3

Christina Demetriadou, Panagiotis Papageorgis + Show 6 more

Open Access

https://doi.org/10.1038/s41419-019-1487-3

Copy DOI

Abstract

N-alpha-acetyltransferase 40 (NAA40) catalyzes the transfer of an acetyl moiety to the alpha-amino group of serine 1 (S1) on histones H4 and H2A. Our previous studies linked NAA40 and its corresponding N-terminal acetylation of histone H4 (N-acH4) to colorectal cancer (CRC). However, the role of NAA40 in CRC development was not investigated. Here, we show that NAA40 protein and mRNA levels are commonly increased in CRC primary tissues compared to non-malignant specimens. Importantly, depletion of NAA40 inhibits cell proliferation and survival of CRC cell lines and increases their sensitivity to 5-Fluorouracil (5-FU) treatment. Moreover, the absence of NAA40 significantly delays the growth of human CRC xenograft tumors. Intriguingly, we found that NAA40 knockdown and loss of N-acH4 reduce the levels of symmetric dimethylation of histone H4 (H4R3me2s) through transcriptional downregulation of protein arginine methyltransferase 5 (PRMT5). NAA40 depletion and subsequent repression of PRMT5 results in altered expression of key oncogenes and tumor suppressor genes leading to inhibition of CRC cell growth. Consistent with this, NAA40 mRNA levels correlate with those of PRMT5 in CRC patient tissues. Taken together, our results establish the oncogenic function of the epigenetic enzyme NAA40 in colon cancer and support its potential as a therapeutic target.

Highlights

In every eukaryotic cell, ~147 base pairs of DNA is wound around four core histone proteins (H3, H4, H2A, and H2B) constructing a nucleosome, which makes up the basic structural unit of chromatin
Meta-analysis of transcriptome data extracted from The Cancer Genome Atlas (TCGA) Genomic Data Commons (GDC) Portal showed that N-alpha-acetyltransferase 40 (NAA40) mRNA levels in colorectal cancer (CRC) patient tissues were significantly higher than those in normal colon tissues (Fig. 1c)
We observed no significant correlation between the different tumor stages of colon adenocarcinoma and NAA40 expression at both the mRNA and protein levels based on the tumor, node, and metastasis classification obtained from the commercially available tissue microarrays and the TCGA network (Supplementary Figure serine 1 (S1))

Summary

Introduction

In every eukaryotic cell, ~147 base pairs of DNA is wound around four core histone proteins (H3, H4, H2A, and H2B) constructing a nucleosome, which makes up the basic structural unit of chromatin. A wide spectrum of chromatin-modifying enzymes, commonly refer to as ‘writers’, decorate the globular domain and N-terminal tails of nucleosomal histones with numerous posttranslational modifications (PTMs)[1]. These PTMs dictate chromatin architecture and tightly regulate DNA-based processes, such as gene expression[2,3]. Unlike all other HATs that acetylate the side chains of internal lysine residues, NAA40 ( known as NatD, Nat[4], or Patt1) catalyzes the addition of an acetyl moiety to the alpha-amino group of the first amino acid residue on histones H4 (N-acH4) and H2A (N-acH2A)[7] This enzyme remained unexplored because it was thought to catalyze a non-regulatory modification. Studies in yeast demonstrated that NAA40 and its Official journal of the Cell Death Differentiation Association

Methods

Results

Conclusion