Chen Jiongyu, Zhuang Yixuan, Wang Ping, Ning Jinfeng, Liu Wei, Huang Yiteng, Lin Xueqiong, Peng Lin, Zhang Donghong
Central Laboratory, Cancer Hospital of Shantou University Medical College, 7 Raoping Road, Shantou, Guangdong, 515041, China.
Guangdong Provincial Key Laboratory of Breast Cancer Diagnosis and Treatment, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, 515041, China.
Cell Death Dis. 2022 Mar 7;13(3):216. doi: 10.1038/s41419-022-04661-8.
DNA N6-methyladenosine (6mA) is a novel epigenetic signaling modification in humans and has been implicated in the progression and tumorigenesis of several cancers. However, the function and mechanism of 6mA in breast cancer (BC), the most common cancer among women, are unclear. Here, we found that decreases in N6AMT1 correlated with the extent of 6mA in clinical BC tissues and predicted a worse survival of BC patients. Functionally, knockdown of N6AMT1 markedly reduced 6mA in DNA and promoted colony formation and migration of BC cells, whereas overexpression of N6AMT1 had the opposite effect. Moreover, silencing of N6AMT1 reduced 6mA modification and enhanced the growth of BC cells in vitro and tumors in vivo. 6mA immunoprecipitation sequencing (6mA-IP-seq), RNA-seq, 6mA-IP-PCR, and bioinformatics analysis indicated that N6AMT1 was a functional methyltransferase for genomic 6mA DNA modifications and related to gene transcriptional activity. Critical negative regulators of the cell cycle, such as RB1, P21, REST, and TP53 were identified as targets of N6AMT1 in BC. These results suggest N6AMT1 enhances DNA 6mA levels to repress tumor progression via transcriptional regulation of cell cycle inhibitors.
DNA N6-甲基腺嘌呤（6mA）是一种在人类中发现的新型表观遗传信号修饰，与多种癌症的进展和肿瘤发生有关。然而，6mA在女性最常见的癌症——乳腺癌（BC）中的功能和机制尚不清楚。在此，我们发现临床BC组织中N6AMT1的降低与6mA的水平相关，并预示着BC患者更差的生存率。在功能上，敲低N6AMT1可显著降低DNA中的6mA水平，并促进BC细胞的集落形成和迁移，而N6AMT1的过表达则产生相反的效果。此外，沉默N6AMT1可降低6mA修饰，并增强BC细胞在体外的生长以及在体内肿瘤的生长。6mA免疫沉淀测序（6mA-IP-seq）、RNA测序、6mA-IP-PCR和生物信息学分析表明，N6AMT1是一种用于基因组6mA DNA修饰的功能性甲基转移酶，且与基因转录活性相关。细胞周期的关键负调节因子，如RB1、P21、REST和TP53被确定为BC中N6AMT1的靶标。这些结果表明，N6AMT1通过对细胞周期抑制剂进行转录调控来提高DNA 6mA水平，从而抑制肿瘤进展。
