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NAA40 Contributes to Colorectal Cancer Growth by Controlling Demetriadou et al. Cell Death and Disease (2019) 10:236 https://doi.org/10.1038/s41419-019-1487-3 Cell Death & Disease ARTICLE Open Access NAA40 contributes to colorectal cancer growth by controlling PRMT5 expression Christina Demetriadou1, Demetria Pavlou1, Fotios Mpekris2, Charis Achilleos3, Triantafyllos Stylianopoulos2, Apostolos Zaravinos 4, Panagiotis Papageorgis4 and Antonis Kirmizis 1 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. 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; Introduction histone proteins. Importantly, deregulation of HAT In every eukaryotic cell, ~147 base pairs of DNA is enzymes significantly alters normal gene expression and is wound around four core histone proteins (H3, H4, H2A, implicated in the development of several diseases and H2B) constructing a nucleosome, which makes up the including cancer4. basic structural unit of chromatin. A wide spectrum of Although an extensive body of work has been accumu- chromatin-modifying enzymes, commonly refer to as lated over the past decades describing the role of many ‘writers’, decorate the globular domain and N-terminal HATs in gene regulation and tumorigenesis, the function of tails of nucleosomal histones with numerous post- some of these enzymes still remains poorly characterized5. translational modifications (PTMs)1. These PTMs dic- One notable example is the N-alpha-acetyltransferase 40 tate chromatin architecture and therefore tightly regulate (NAA40) enzyme that belongs to the N-terminal acetyl- DNA-based processes, such as gene expression2,3. Histone transferase (NAT) family of enzymes sharing the conserved acetyltransferases (HATs) constitute one of the most sequence motif of the GCN5-related acetyltransferase extensively studied group of epigenetic writers, which superfamily6. Unlike all other HATs that acetylate the side modify chromatin via the deposition of acetyl-groups on chains of internal lysine residues, NAA40 (also known as NatD, Nat4, or Patt1) catalyzes the addition of an acetyl moiety to the alpha-amino group of the first amino acid Correspondence: Antonis Kirmizis ([email protected]) 7 1Epigenetics Laboratory, Department of Biological Sciences, University of residue on histones H4 (N-acH4) and H2A (N-acH2A) . Cyprus, 2109 Nicosia, Cyprus For years, this enzyme remained unexplored because it was 2 Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing thought to catalyze a non-regulatory modification. Intrigu- Engineering, University of Cyprus, 1678 Nicosia, Cyprus Full list of author information is available at the end of the article. ingly, studies in yeast demonstrated that NAA40 and its Edited by P. Pinton © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a linktotheCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Official journal of the Cell Death Differentiation Association Demetriadou et al. Cell Death and Disease (2019) 10:236 Page 2 of 14 catalyzed N-acH4 regulate the expression of specificsetsof relevance of NAA40 expression in patients with CRC, we genes controlling cell growth8,9. In support of this identified initially examined NAA40 protein levels on tissue cellular function, several other studies have implicated microarrays harboring colon cancer tissues and adjacent NAA40 deregulation in the development and progression of normal specimens. Immunofluorescence analysis showed different types of malignancy. In particular, a recent study that NAA40 is increased in colon adenocarcinomas has indicated that NAA40 is a critical regulator of cell compared to benign lesions and normal colon specimens invasion during lung cancer metastasis10.Moreover, (Fig. 1a). In particular, the positive rates of NAA40 stain- NAA40 was shown to be downregulated in hepatocellular ing were 11%, 44%, and 64% for normal colon samples, carcinoma tissues and ectopic NAA40 expression sensitizes benign tumors (polyps and adenomas), and adenocarci- hepatoma cancer cell lines to drug-induced apoptosis11. nomas, respectively (Fig. 1b). Consistently, meta-analysis Conversely, we have previously unveiled a pro-survival role of transcriptome data extracted from The Cancer Gen- for NAA40 in colorectal cancer (CRC) cells suggesting that ome Atlas (TCGA) GDC Portal showed that NAA40 it may stimulate cancer cell growth12. Despite the above mRNA levels in CRC patient tissues were significantly evidence, the contribution of NAA40 in colorectal carci- higher than those in normal colon tissues (Fig. 1c). nogenesis remained unclear. However, we observed no significant correlation between Histone-modifying enzymes often cross-regulate each the different tumor stages of colon adenocarcinoma and other in order to generate a highly dynamic interplay NAA40 expression at both the mRNA and protein levels amongst histone modifications, which is important in based on the tumor, node, and metastasis classification defining gene expression patterns13,14. Consistent with obtained from the commercially available tissue micro- this notion, we have previously reported that NAA40 and arrays and the TCGA network (Supplementary Figure S1). its mediated N-acH4 inhibit the activity of the histone This may suggest that NAA40 upregulation occurs from arginine methyltransferase HMT1 toward arginine 3 of the initial stages of malignant progression and is sustained histone H4 (H4R3) to control ribosomal gene expression along the different tumor stages. Overall, these results in yeast9. In human cells, H4R3 is targeted by various demonstrate that elevated NAA40 expression is a fre- protein arginine methyltransferases (PRMTs) resulting in quent event in colorectal carcinogenesis. different methylation states. Specifically, PRMT1 catalyzes asymmetric dimethylation of H4R3 (H4R3me2a), PRMT5 Loss of NAA40 inhibits the growth of CRC cells in vitro deposits symmetric dimethylation to form H4R3me2s and To further evaluate the role of NAA40 in the context of PRMT7 also mediates H4R3me2s but mainly mono- CRC cell growth, we constructed an inducible system to methylates this histone residue to form H4R3me115. downregulate NAA40 upon doxycycline (dox) treatment Interestingly, deregulation of these H4R3-associated of HCT116, HT-29, SW480, and SW620 colon cancer cell PRMTs has been intimately linked to carcinogenesis, lines. For this purpose we used two different lentivirus- including CRC, through transcriptional control of genes based shRNA sequences (NAA40-KD1 and NAA40-KD2) implicated in diverse cellular processes, such as cell pro- targeting two distinct sites of NAA40 mRNA. Dox liferation, DNA repair, and apoptosis16,17. Although we administration in all engineered cell lines significantly have previously reported an interplay between NAA40- reduced NAA40 mRNA levels in the NAA40-KD1 and mediated histone acetylation and H4R3 methylation in NAA40-KD2 cells compared to the negative scrambled yeast9, this crosstalk has not yet been investigated in control (SCR) cells as indicated by quantitative real-time mammalian cells. PCR (qRT-PCR) (Fig. 2a). Accordingly, western blot In this study, we show that NAA40 is significantly analysis showed substantial decrease of NAA40 protein upregulated in primary CRC tissues and promotes CRC levels in all four cell lines tested upon dox-mediated cell growth both in vitro and in xenograft tumor models. induction of both NAA40 shRNAs as opposed to the The results also indicate that in CRC cells NAA40 reg- induction of the control SCR shRNA (Fig. 2b). ulates H4R3me2s levels through transcriptional
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