Fei Xie, Saiwei Hua, Yajuan Guo, Taoyuan Wang, Changliang Shan, Lianwen Zhang, Tao He
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引用次数: 0
Abstract
Breast cancer (BC) is the most frequently diagnosed cancer and the primary cause of cancer-related mortality in women. Treatment of triple-negative breast cancer (TNBC) remains particularly challenging due to its resistance to chemotherapy and poor prognosis. Extensive research efforts in BC screening and therapy have improved clinical outcomes for BC patients. Therefore, identifying reliable biomarkers for TNBC is of great clinical importance. Here, we found that tyrosine aminotransferase (TAT) expression was significantly reduced in BC and strongly correlated with the poor prognosis of BC patients, which distinguished BC patients from normal individuals, indicating that TAT is a valuable biomarker for early BC diagnosis. Mechanistically, we uncovered that methylation of the TAT promoter was significantly increased by DNA methyltransferase 3 (DNMT3A/3B). In addition, reduced TAT contributes to DNA replication and cell cycle activation by regulating homologous recombination repair and mismatch repair to ensure genomic stability, which may be one of the reasons for TNBC resistance to chemotherapy. Furthermore, we demonstrated that Diazinon increases TAT expression as an inhibitor of DNMT3A/3B and inhibits the growth of BC by blocking downstream pathways. Taken together, we revealed that TAT is silenced by DNMT3A/3B in BC, especially in TNBC, which promotes the proliferation of tumor cells by supporting DNA replication, activating cell cycle, and enhancing DNA damage repair. These results provide fresh insights and a theoretical foundation for the clinical diagnosis and treatment of BC.
乳腺癌(BC)是最常诊断出的癌症,也是导致女性癌症相关死亡的主要原因。由于三阴性乳腺癌(TNBC)对化疗的耐药性和不良预后,其治疗仍然特别具有挑战性。在乳腺癌筛查和治疗方面开展的大量研究工作改善了乳腺癌患者的临床预后。因此,确定 TNBC 的可靠生物标志物具有重要的临床意义。在这里,我们发现酪氨酸氨基转移酶(TAT)在BC中的表达明显降低,并与BC患者的不良预后密切相关,这将BC患者与正常人区分开来,表明TAT是早期诊断BC的一个有价值的生物标志物。从机理上讲,我们发现 DNA 甲基转移酶 3(DNMT3A/3B)会显著增加 TAT 启动子的甲基化。此外,TAT的减少通过调节同源重组修复和错配修复来确保基因组稳定性,从而促进DNA复制和细胞周期激活,这可能是TNBC耐化疗的原因之一。此外,我们还证明了地嗪农作为 DNMT3A/3B 的抑制剂会增加 TAT 的表达,并通过阻断下游通路抑制 BC 的生长。综上所述,我们发现在 BC 中,尤其是在 TNBC 中,TAT 被 DNMT3A/3B 沉默,而 DNMT3A/3B 通过支持 DNA 复制、激活细胞周期和增强 DNA 损伤修复促进肿瘤细胞的增殖。这些结果为BC的临床诊断和治疗提供了新的见解和理论基础。
BiomoleculesBiochemistry, Genetics and Molecular Biology-Molecular Biology
CiteScore
9.40
自引率
3.60%
发文量
1640
审稿时长
18.28 days
期刊介绍:
Biomolecules (ISSN 2218-273X) is an international, peer-reviewed open access journal focusing on biogenic substances and their biological functions, structures, interactions with other molecules, and their microenvironment as well as biological systems. Biomolecules publishes reviews, regular research papers and short communications. Our aim is to encourage scientists to publish their experimental and theoretical results in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced.