NAT10介导ac^(4)C乙酰化修饰促进乳腺癌细胞的增殖和迁移能力  

NAT10-mediated ac^(4)C acetylation promotes the proliferation and migration of breast cancer cells

作　　者：农巧红[1] 余少康[1] 卢婵妃 庄雪寒 杨子健 NONG Qiaohong;YU Shaokang;LU Chanfei;ZHUANG Xuehan;YANG Zijian(Department of Oncology,Peking University Shenzhen Hospital,Shenzhen,Guangdong 518036,China;Department of Breast and Thyroid Surgery,Peking University Shenzhen Hospital,Shenzhen,Guangdong 518036,China)

机构地区：[1]北京大学深圳医院肿瘤科,广东深圳518036 [2]北京大学深圳医院乳腺甲状腺外科,广东深圳518036

出　　处：《中国优生与遗传杂志》2024年第9期1777-1790,共14页Chinese Journal of Birth Health & Heredity

摘　　要：目的探究N-乙酰基转移酶10(NAT10)介导4-乙酰胞苷(ac^(4)C)乙酰化修饰促进乳腺癌细胞的增殖和迁移能力的具体机制。方法收集80例乳腺癌及对应癌旁组织,检测组织、细胞系NAT10表达与ac^(4)C修饰水平,分析NAT10表达与乳腺癌临床病理特征的关系。通过体外细胞实验检测SKBR-3、BT474细胞增殖、迁移、侵袭能力与细胞周期变化,体内异种移植实验测定细胞成瘤能力,检测移植瘤Ki-67表达,观察肝、肺部肿瘤结节形成情况。分析NAT10介导ac^(4)C乙酰化修饰的基因表达谱,验证NAT10通过ac^(4)C修饰对KIF23表达的影响,检测NAT10/KIF23/GSK-3β轴、Wnt/β-catenin信号通路相关蛋白表达。结果乳腺癌组织、细胞系NAT10表达水平、ac^(4)C修饰水平均高于癌旁组织、MCF-10A(P<0.05),NAT10表达与肿瘤分期、淋巴结转移、远处转移、分化程度、Ki-67阳性率相关(P<0.05)。抑制NAT10表达能够抑制SKBR-3细胞增殖、迁移、侵袭能力,阻滞细胞周期,降低体内成瘤与转移能力,过表达NAT10则能促进BT474细胞的恶性生物学行为。KIF23为存在ac^(4)C修饰的NAT10的直接靶点,二者表达水平正相关(r=0.3624,P=0.0010)。抑制或过表达NAT10均会对NAT10和KIF23之间的相互作用、KIF23 mRNA ac^(4)C修饰造成影响(P<0.05)。抑制NAT10同时过表达KIF23或过表达NAT10同时抑制KIF23能够逆转NAT10表达水平变化对SKBR-3、BT474细胞增殖、迁移、侵袭、周期以及Wnt/β-catenin信号通路相关蛋白表达的影响。结论NAT10介导ac^(4)C乙酰化修饰增强KIF23表达,NAT10/KIF23/GSK-3β轴通过调节Wnt/β-catenin信号通路促进乳腺癌发生发展。Objective To investigate the specific mechanism of N-acetyltransferase 10(NAT10)-mediated acetylation modification of N4-acetylcytidine(ac^(4)C)promoting the proliferation and migration of breast cancer cells.Methods 80 cases of breast cancer and corresponding paracancerous tissues were collected.The expression of NAT10 and the level of ac^(4)C modification in tissues and cell lines were detected.The relationship between NAT10 expression and clinicopathological features of breast cancer was analyzed.The proliferation,migration,invasion capabilities,and cell cycle changes of SKBR-3 and BT474 cells were evaluated through in vitro cell experiments.The tumorigenic capacity of cells was determined through xenograft experiments in vivo,with the expression of Ki-67 in transplanted tumors detected and the formation of tumor nodules in the liver and lungs observed.The gene expression profile mediated by NAT10-induced ac^(4)C acetylation modification was analyzed,and the effect of NAT10 on KIF23 expression through ac^(4)C modification was verified.The expression of proteins related to the NAT10/KIF23/GSK-3βaxis and the Wnt/β-catenin signaling pathway was detected.Results The expression level of NAT10 and the level of ac^(4)C modification in breast cancer tissues and cell lines were higher than those in paracancerous tissues and MCF-10A cells(P<0.05).The expression of NAT10 was correlated with tumor stage,lymphatic metastasis,distant metastasis,degree of differentiation,and Ki-67 positivity rate(P<0.05).Inhibiting NAT10 expression was found to suppress the proliferation,migration,and invasion capabilities of SKBR-3 cells,arrest cell cycle progression,and reduce tumorigenicity and metastasis ability in vivo.Conversely,overexpressing NAT10 promoted the malignant biological behavior of BT474 cells.KIF23 was identified as a direct target of NAT10 with ac^(4)C modification,and a positive correlation was observed between the expression levels of the two proteins(r=0.3624,P=0.0010).Both inhibition and overexpression of NAT10 wer

关 键 词：N-乙酰基转移酶10 4-乙酰胞苷 乙酰化修饰 乳腺癌 驱动蛋白家族成员23 

分 类 号：R737.9[医药卫生—肿瘤]