School of Biomedical Sciences, University of Queensland, St. Lucia, Australia.
School of Biomedical Sciences, University of Queensland, St. Lucia, Australia
Mol Pharmacol. 2019 Nov;96(5):573-579. doi: 10.1124/mol.119.117432. Epub 2019 Aug 23.
Arylamine -acetyltransferase 1 (NAT1) is a drug-metabolizing enzyme that influences cancer cell proliferation and survival. However, the mechanism for these effects is unknown. Because of previous observations that NAT1 inhibition decreases invasiveness, we investigated the expression of the metalloproteinase matrix metalloproteinase 9 (MMP9) in human breast cancer samples and in cancer cells. We found a negative correlation between the expression of NAT1 and MMP9 in 1904 breast cancer samples. Moreover, when NAT1 was deleted in highly invasive breast cancer cells, MMP9 mRNA and protein significantly increased, both of which were reversed by reintroducing NAT1 into the knockout cells. After NAT1 deletion, there was an increased association of acetylated histone H3 with the SET and MYND-domain containing 3 (SMYD3) element in the MMP9 promoter, consistent with an increase in MMP9 transcription. NAT1 deletion also up-regulated hypoxia-inducible factor 1-α (HIF1-). Treatment of the NAT1 knockout cells with small interfering RNA directed toward HIF1- mRNA inhibited the increased expression of MMP9. Taken together, these results show a direct inverse relationship between NAT1 and MMP9 and suggest that HIF1- may be essential for the regulation of MMP9 expression by NAT1. SIGNIFICANCE STATEMENT: The expression of the enzyme NAT1 was found to be negatively correlated with MMP9 expression in tumor tissue from breast cancer patients. In cells, NAT1 regulated MMP9 expression at a transcriptional level via HIF1-. This finding is important as it may explain some of the pathological features associated with changes in NAT1 expression in cancer.
芳香胺-N-乙酰基转移酶 1（NAT1）是一种药物代谢酶，可影响癌细胞的增殖和存活。然而，这些作用的机制尚不清楚。由于先前观察到 NAT1 抑制可降低侵袭性，因此我们研究了人类乳腺癌样本和癌细胞中金属蛋白酶基质金属蛋白酶 9（MMP9）的表达。我们发现 1904 例乳腺癌样本中 NAT1 和 MMP9 的表达呈负相关。此外，当高度侵袭性乳腺癌细胞中 NAT1 缺失时，MMP9mRNA 和蛋白质显著增加，而将 NAT1 重新引入敲除细胞中则逆转了这一现象。NAT1 缺失后，MMP9 启动子中乙酰化组蛋白 H3 与 SET 和 MYND 结构域包含 3（SMYD3）元件的结合增加，这与 MMP9 转录增加一致。NAT1 缺失还上调了缺氧诱导因子 1-α（HIF1-α）。用针对 HIF1-αmRNA 的小干扰 RNA 处理 NAT1 敲除细胞可抑制 MMP9 表达的增加。总之，这些结果表明 NAT1 与 MMP9 之间存在直接的负相关关系，并表明 HIF1-α可能是 NAT1 调节 MMP9 表达所必需的。这些发现具有重要意义，因为它可能解释了与癌症中 NAT1 表达变化相关的一些病理特征。
