Department of Biology, The Catholic University of America, Washington, District of Columbia, United States of America.
Department of Biochemistry and Molecular Biology, Howard University College of Medicine, Washington, District of Columbia, United States of America.
Sci Rep. 2019 Oct 10;9(1):14650. doi: 10.1038/s41598-019-51195-9.
Keratin 19 (K19) belongs to the keratin family of proteins, which maintains structural integrity of epithelia. In cancer, K19 is highly expressed in several types where it serves as a diagnostic marker. Despite the positive correlation between higher expression of K19 in tumor and worse patient survival, the role of K19 in breast cancer remains unclear. Therefore, we ablated K19 expression in MCF7 breast cancer cells and found that K19 was required for cell proliferation. Transcriptome analyses of KRT19 knockout cells identified defects in cell cycle progression and levels of target genes of E2F1, a key transcriptional factor for the transition into S phase. Furthermore, proper levels of cyclin dependent kinases (CDKs) and cyclins, including D-type cyclins critical for E2F1 activation, were dependent on K19 expression, and K19-cyclin D co-expression was observed in human breast cancer tissues. Importantly, K19 interacts with cyclin D3, and a loss of K19 resulted in decreased protein stability of cyclin D3 and sensitivity of cells towards CDK inhibitor-induced cell death. Overall, these findings reveal a novel function of K19 in the regulation of cell cycle program and suggest that K19 may be used to predict the efficacy of CDK inhibitors for treatments of breast cancer.
角蛋白 19（K19）属于角蛋白蛋白家族，可维持上皮组织的结构完整性。在癌症中，K19 在几种类型中高度表达，可作为诊断标志物。尽管肿瘤中 K19 表达水平较高与患者生存状况较差呈正相关，但 K19 在乳腺癌中的作用仍不清楚。因此，我们在 MCF7 乳腺癌细胞中敲除了 K19 表达，发现 K19 对于细胞增殖是必需的。KRT19 敲除细胞的转录组分析表明，细胞周期进程存在缺陷，E2F1 的靶基因水平也存在缺陷，E2F1 是进入 S 期的关键转录因子。此外，细胞周期蛋白依赖性激酶（CDKs）和细胞周期蛋白（包括对 E2F1 激活至关重要的 D 型细胞周期蛋白）的适当水平依赖于 K19 的表达，并且在人乳腺癌组织中观察到 K19-细胞周期蛋白 D 共表达。重要的是，K19 与细胞周期蛋白 D3 相互作用，K19 的缺失导致细胞周期蛋白 D3 的蛋白稳定性降低，并使细胞对 CDK 抑制剂诱导的细胞死亡敏感。总的来说，这些发现揭示了 K19 在调节细胞周期程序中的新功能，并表明 K19 可用于预测 CDK 抑制剂治疗乳腺癌的疗效。
