Yang Shan, Cheng Meng, Zhang Shaonan, Wang Haoqi, Wang Jiaxing, Zhang Xi, Mi Yunzhe, Li Sainan
Department of Breast Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
Hebei Key Laboratory of Breast Cancer Molecular Medicine, Shijiazhuang, Hebei, China.
PLoS One. 2025 May 5;20(5):e0321889. doi: 10.1371/journal.pone.0321889. eCollection 2025.
ADAMTS8 inactivation by epigenetic modifications has been reported in various tumors, and the dysregulation of ADAMTS8 expression is associated with poor clinical outcomes, cancer cell invasion, and metastasis. De novo methylation, involving DNMT3A, plays an important role in cancer development; however, it remains unclear whether DNMT3A regulates the progressive expression of breast cancer by regulating ADAMTS8. Through published cancer-related datasets and clinical validation, we found that ADAMTS8 and DNMT3A expression negatively correlated in breast cancer, and both associated with patient prognosis. Related cell experiments have shown that DNMT3A overexpression promotes breast cancer cell proliferation, migration, invasion, and apoptosis, whereas silencing DNMT3A has the opposite effect. Through Co-IP experiments, we confirmed that DNMT3A binds directly to ADAMTS8. Methylation-specific PCR (MSP) experiments confirmed that DNMT3A mediates ADAMTS8 promoter methylation in breast cancer. In addition, DNMT3A activated the EGFR-MEK-ERK signaling pathway by effectively downregulating ADAMTS8, whereas silencing ADAMTS8 effectively inhibited this signaling pathway. Taken together, our findings suggest that DNMT3A activates the EGFR-MEK-ERK signaling pathway by silencing ADAMTS8 transcription through methylation, thereby promoting breast cancer development. Therefore, DNMT3A may serve as an inhibitory target in breast cancer-targeted therapy.
已有报道称，表观遗传修饰可使多种肿瘤中的ADAMTS8失活，且ADAMTS8表达失调与不良临床预后、癌细胞侵袭和转移相关。涉及DNA甲基转移酶3A（DNMT3A）的从头甲基化在癌症发展中起重要作用；然而，DNMT3A是否通过调节ADAMTS8来调控乳腺癌的进展性表达仍不清楚。通过已发表的癌症相关数据集和临床验证，我们发现ADAMTS8和DNMT3A在乳腺癌中的表达呈负相关，且二者均与患者预后相关。相关细胞实验表明，过表达DNMT3A可促进乳腺癌细胞增殖、迁移、侵袭及凋亡，而沉默DNMT3A则产生相反效果。通过免疫共沉淀实验，我们证实DNMT3A可直接与ADAMTS8结合。甲基化特异性PCR（MSP）实验证实，DNMT3A在乳腺癌中介导ADAMTS8启动子甲基化。此外，DNMT3A通过有效下调ADAMTS8激活表皮生长因子受体（EGFR）-丝裂原活化蛋白激酶激酶（MEK）-细胞外信号调节激酶（ERK）信号通路，而沉默ADAMTS8则有效抑制该信号通路。综上所述，我们的研究结果表明，DNMT3A通过甲基化沉默ADAMTS8转录来激活EGFR-MEK-ERK信号通路，从而促进乳腺癌发展。因此，DNMT3A可能成为乳腺癌靶向治疗的抑制靶点。
