Abstract
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.
Highlights
Keratins are expressed predominantly in epithelial cells and as members of the intermediate filament family of proteins, they are part of the largest family of cytoskeletal proteins[1]
Experiments were carried out using two different KRT19 KO clones (KO1 and KO2) to assess the effects of Keratin 19 (K19) ablation. Both western blotting (Fig. 1a) and quantitative RT-PCR (Fig. 1b) confirmed the loss of K19 expression in MCF7 KRT19 KO cell lines. These losses were specific to K19 as expression of K8 and K18, two other keratins expressed in MCF7 cells[4] remained unaffected compared to the wild type parental control (Fig. 1a)
We discovered that K19 plays a critical role in the proliferation of MCF7 breast cancer cells
Summary
Keratins are expressed predominantly in epithelial cells and as members of the intermediate filament family of proteins, they are part of the largest family of cytoskeletal proteins[1]. Keratins are widely used as diagnostic markers to detect tumors in both primary and distal sites and to determine tumors’ tissue of origin in order to aid in treatment strategies[6]. In this regard, K19 has been useful because it is among the most sensitive diagnostic markers across a broad range of cancer types[6]. In studies using breast cancer cells, K19 has shown that it can either suppress cancer cell proliferation, migration and invasion[17,18,19] or promote tumor growth and metastasis[20,21]
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