Department of VIP Ward, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy (Tianjin), Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China.
The First Department of Breast Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy (Tianjin), Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China.
Thorac Cancer. 2024 Apr;15(10):820-829. doi: 10.1111/1759-7714.15262. Epub 2024 Feb 26.
N-acetyltransferase 10 (NAT10) serves as a critical enzyme in mediating the N4-acetylcytidine (ac4C) that ensures RNA stability and effective translation processes. The role of NAT10 in driving the advancement of breast cancer remains uninvestigated.
We observed an increase in NAT10 expression, both at mRNA level through the analysis of the Cancer Genome Atlas (TCGA) database and at the protein level of tumor tissues from breast cancer patients. We determined that a heightened expression of NAT10 served as a predictor of an unfavorable clinical outcome. By screening the Cancer Cell Line Encyclopedia (CCLE) cell bank, this expression pattern of NAT10 was consistency found across almost all the classic breast cancer cell lines.
Functionally, interference of NAT10 expression exerts an inhibitory effect on proliferation and invasion of breast cancer cells. By using ac4C RNA immunoprecipitation (ac4c-RIP) and acRIP-qPCR assays, we identified a reduction of ac4C enrichment within the ATP binding cassette (ABC) transporters, multidrug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP), consequent to NAT10 suppression. Expressions of MDR1 and BCRP exhibited a positive correlation with NAT10 expression in tumor tissues, and the inhibition of NAT10 in breast cancer cells resulted in a decrease of MDR1 and BCRP expression. Therefore, the overexpressing of MDR1 and BCRP could partially rescue the adverse consequences of NAT10 depletion. In addition, we found that, remodelin, a NAT10 inhibitor, reinstated the susceptibility of capecitabine-resistant breast cancer cells to the chemotherapy, both in vitro and in vivo.
The results of our study demonstrated the essential role of NAT10-mediated ac4c-modification in breast cancer progression and provide a novel strategy for overcoming chemoresistance challenges.
N-乙酰基转移酶 10（NAT10）作为一种关键酶，介导 N4-乙酰胞苷（ac4C），确保 RNA 稳定性和有效的翻译过程。NAT10 在推动乳腺癌进展中的作用尚未得到研究。
我们观察到 NAT10 的表达增加，在 TCGA 数据库中通过分析 mRNA 水平和乳腺癌患者肿瘤组织的蛋白水平都观察到了这一点。我们确定 NAT10 的高表达是预后不良的预测因子。通过筛选癌症细胞系百科全书（CCLE）细胞库，发现几乎所有经典的乳腺癌细胞系都存在这种 NAT10 的表达模式。
功能上，干扰 NAT10 的表达对乳腺癌细胞的增殖和侵袭具有抑制作用。通过使用 ac4C RNA 免疫沉淀（ac4c-RIP）和 acRIP-qPCR 测定，我们发现 NAT10 抑制后，ABC 转运蛋白、多药耐药蛋白 1（MDR1）和乳腺癌耐药蛋白（BCRP）中的 ac4C 富集减少。肿瘤组织中 MDR1 和 BCRP 的表达与 NAT10 的表达呈正相关，乳腺癌细胞中 NAT10 的抑制导致 MDR1 和 BCRP 的表达下降。因此，MDR1 和 BCRP 的过表达可以部分挽救 NAT10 耗竭的不良后果。此外，我们发现，NAT10 抑制剂 remodelin 可恢复耐卡培他滨的乳腺癌细胞对化疗的敏感性，无论是在体外还是体内。
我们的研究结果表明，NAT10 介导的 ac4c 修饰在乳腺癌进展中起着重要作用，并为克服化疗耐药性挑战提供了一种新的策略。
