College of Pharmacy, Natural Products Research Institute, Seoul National University, Seoul 08826, Korea.
College of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Korea.
Biomolecules. 2020 Mar 31;10(4):530. doi: 10.3390/biom10040530.
Triple-negative breast cancer (TNBC) is among the most aggressive and potentially metastatic malignancies. Most affected patients have poor clinical outcomes due to the lack of specific molecular targets on tumor cells. The upregulated expression of disruptor of telomeric silencing 1-like (DOT1L), a histone methyltransferase specific for the histone H3 lysine 79 residue (H3K79), is strongly correlated with TNBC cell aggressiveness. Therefore, DOT1L is considered a potential molecular target in TNBC. Fluoro-neplanocin A (F-NepA), an inhibitor of -adenosylhomocysteine hydrolase, exhibited potent antiproliferative activity against various types of cancer cells, including breast cancers. However, the molecular mechanism underlying the anticancer activity of F-NepA in TNBC cells remains to be elucidated. We determined that F-NepA exhibited a higher growth-inhibitory activity against TNBC cells relative to non-TNBC breast cancer and normal breast epithelial cells. Moreover, F-NepA effectively downregulated the level of H3K79me2 in MDA-MB-231 TNBC cells by inhibiting DOT1L activity. F-NepA also significantly inhibited TNBC cell migration and invasion. These activities of F-NepA might be associated with the upregulation of E-cadherin and downregulation of N-cadherin and Vimentin in TNBC cells. Taken together, these data highlight F-NepA as a strong potential candidate for the targeted treatment of high-DOT1L-expressing TNBC.
三阴性乳腺癌（TNBC）是最具侵袭性和潜在转移性的恶性肿瘤之一。由于肿瘤细胞缺乏特异性分子靶点，大多数受影响的患者临床预后较差。破坏端粒沉默 1 样蛋白（DOT1L）的上调表达，一种特异性针对组蛋白 H3 赖氨酸 79 残基（H3K79）的组蛋白甲基转移酶，与 TNBC 细胞的侵袭性密切相关。因此，DOT1L 被认为是 TNBC 的潜在分子靶点。氟代-neplanocin A（F-NepA），一种腺苷同型半胱氨酸水解酶抑制剂，对包括乳腺癌在内的多种类型的癌细胞表现出强大的抗增殖活性。然而，F-NepA 在 TNBC 细胞中的抗癌活性的分子机制仍有待阐明。我们确定 F-NepA 对 TNBC 细胞的生长抑制活性相对于非 TNBC 乳腺癌和正常乳腺上皮细胞更高。此外，F-NepA 通过抑制 DOT1L 活性，有效下调 MDA-MB-231 TNBC 细胞中 H3K79me2 的水平。F-NepA 还显著抑制 TNBC 细胞的迁移和侵袭。F-NepA 的这些活性可能与 TNBC 细胞中 E-钙粘蛋白的上调和 N-钙粘蛋白和波形蛋白的下调有关。综上所述，这些数据强调了 F-NepA 作为一种针对高表达 DOT1L 的 TNBC 的潜在有效治疗药物。
