State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of life Science and Technology, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, Jiangsu province, China.
Department of Breast Surgery, Breast Disease Center of Jiangsu Province, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu province, China.
Cell Death Dis. 2019 Feb 21;10(3):176. doi: 10.1038/s41419-019-1437-0.
Breast cancer is the most prevalent cancer in women worldwide, which remains incurable once metastatic. Breast cancer stem cells (BCSCs) are a small subset of breast cancer cells which are essential in tumor formation, metastasis, and drug resistance. microRNAs (miRNAs) play important roles in the breast cancer cells and BCSCs by regulating specific genes. In this study, we found that miR-29a was up-regulated in BCSCs, in aggressive breast cancer cell line and in breast cancer tissues. We also confirmed suppressor of variegation 4-20 homolog 2 (SUV420H2), which is a histone methyltransferase that specifically trimethylates Lys-20 of histone H4 (H4K20), as the target of miR-29a. Both miR-29a overexpression and SUV420H2 knockdown in breast cancer cells promoted their migration and invasion in vitro and in vivo. Furthermore, we discovered that SUV420H2-targeting miR-29a attenuated the repression of connective tissue growth factor (CTGF) and growth response protein-1 (EGR1) by H4K20 trimethylation and promoted the EMT progress of breast cancer cells. Taken together, our findings reveal that miR-29a plays critical roles in the EMT and metastasis of breast cancer cells through targeting SUV420H2. These findings may provide new insights into novel molecular therapeutic targets for breast cancer.
乳腺癌是全球女性最常见的癌症，一旦发生转移就无法治愈。乳腺癌干细胞（BCSCs）是乳腺癌细胞中的一小部分，对于肿瘤的形成、转移和耐药性至关重要。microRNAs（miRNAs）通过调节特定基因在乳腺癌细胞和 BCSCs 中发挥重要作用。在这项研究中，我们发现 miR-29a 在 BCSCs、侵袭性乳腺癌细胞系和乳腺癌组织中上调。我们还证实了抑制变异 4-20 同源物 2（SUV420H2），一种特异性三甲基化组蛋白 H4 赖氨酸 20（H4K20）的组蛋白甲基转移酶，是 miR-29a 的靶标。乳腺癌细胞中 miR-29a 的过表达和 SUV420H2 的敲低均可促进其体外和体内迁移和侵袭。此外，我们发现 SUV420H2 靶向 miR-29a 减弱了 H4K20 三甲基化对结缔组织生长因子（CTGF）和生长反应蛋白 1（EGR1）的抑制作用，并促进了乳腺癌细胞的 EMT 进展。总之，我们的研究结果表明，miR-29a 通过靶向 SUV420H2 在乳腺癌细胞的 EMT 和转移中发挥关键作用。这些发现可能为乳腺癌的新型分子治疗靶点提供新的见解。
