Breast cancer is often sporadic due to several factors. Among them, the deregulation of epigenetic proteins may be involved. TIP60 or KAT5 is an acetyltransferase that regulates gene transcription through the chromatin structure. This pleiotropic protein acts in several cellular pathways by acetylating proteins. RNA and protein expressions of TIP60 were shown to decrease in some breast cancer subtypes, particularly in triple-negative breast cancer (TNBC), where a low expression of TIP60 was exhibited compared with luminal subtypes. In this study, the inhibition of the residual activity of TIP60 in breast cancer cell lines was investigated by using two chemical inhibitors, TH1834 and NU9056, first on the acetylation of the specific target, lysine 4 of histone 3 (H3K4) by immunoblotting, and second, by chromatin immunoprecipitation (ChIP)-qPCR (-quantitative Polymerase Chain Reaction). Subsequently, significant decreases or a trend toward decrease of H3K4ac in the different chromatin compartments were observed. In addition, the expression of 48 human nuclear receptors was studied with TaqMan Low-Density Array in these breast cancer cell lines treated with TIP60 inhibitors. The statistical analysis allowed us to comprehensively characterize the androgen receptor and NR3C2 receptors in TNBC cell lines after TH1834 or NU9056 treatment. The understanding of the residual activity of TIP60 in the evolution of breast cancer might be a major asset in the fight against this disease, and could allow TIP60 to be used as a biomarker or therapeutic target for breast cancer progression in the future.

中文翻译：

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深入研究乳腺癌表观遗传学：从体外化学抑制组蛋白乙酰转移酶 TIP60 的见解。

由于多种因素，乳腺癌通常是散发性的。其中，可能涉及表观遗传蛋白的失调。TIP60 或 KAT5 是一种乙酰转移酶，通过染色质结构调节基因转录。这种多效性蛋白质通过乙酰化蛋白质在几种细胞途径中起作用。TIP60 的 RNA 和蛋白质表达在某些乳腺癌亚型中降低，特别是在三阴性乳腺癌 (TNBC) 中，与管腔亚型相比，TIP60 的表达较低。在这项研究中，通过使用两种化学抑制剂 TH1834 和 NU9056，首先通过免疫印迹对特定靶点组蛋白 3 (H3K4) 的赖氨酸 4 的乙酰化，研究了 TIP60 在乳腺癌细胞系中的残留活性的抑制作用。第二，通过染色质免疫沉淀 (ChIP)-qPCR（定量聚合酶链反应）。随后，观察到不同染色质隔室中 H3K4ac 的显着减少或减少趋势。此外，在这些用 TIP60 抑制剂处理的乳腺癌细胞系中，使用 TaqMan 低密度阵列研究了 48 种人类核受体的表达。统计分析使我们能够全面表征雄激素受体和TH1834或 NU9056 处理后 TNBC 细胞系中的NR3C2受体。了解 TIP60 在乳腺癌演变过程中的残留活性可能是对抗这种疾病的重要资产，并且可以使 TIP60 在未来用作乳腺癌进展的生物标志物或治疗靶点。