Epigenetics Laboratory, Department of Biological Sciences, University of Cyprus, 2109, Nicosia, Cyprus.
Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, 1678, Nicosia, Cyprus.
Cell Death Dis. 2019 Mar 11;10(3):236. doi: 10.1038/s41419-019-1487-3.
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.
N-α-乙酰基转移酶 40（NAA40）催化将乙酰基转移到组蛋白 H4 和 H2A 的丝氨酸 1（S1）的α-氨基上。我们之前的研究将 NAA40 及其对应的组蛋白 H4 的 N-末端乙酰化（N-acH4）与结直肠癌（CRC）联系起来。然而，NAA40 在 CRC 发展中的作用尚未得到研究。在这里，我们表明与非恶性标本相比，CRC 原发性组织中 NAA40 蛋白和 mRNA 水平普遍升高。重要的是，NAA40 的耗竭抑制了 CRC 细胞系的细胞增殖和存活，并增加了它们对 5-氟尿嘧啶（5-FU）治疗的敏感性。此外，NAA40 的缺失显著延迟了人 CRC 异种移植肿瘤的生长。有趣的是，我们发现 NAA40 敲低和 N-acH4 的缺失通过蛋白精氨酸甲基转移酶 5（PRMT5）的转录下调降低了组蛋白 H4 的对称二甲基化（H4R3me2s）的水平。NAA40 的耗竭和随后的 PRMT5 抑制导致关键癌基因和肿瘤抑制基因的表达改变，从而抑制 CRC 细胞的生长。与此一致的是，NAA40 mRNA 水平与 CRC 患者组织中的 PRMT5 水平相关。总之，我们的结果确立了表观遗传酶 NAA40 在结肠癌中的致癌功能，并支持其作为治疗靶点的潜力。
