Abstract
The cyclin-dependent kinases CDK4 and CDK6 promote progression through the cell cycle, where their functions are considered to be redundant. Recent studies have identified an additional role for CDK6 in the transcriptional regulation of cancer-relevant genes such as VEGF-A and EGR1 in hematopoietic malignancies. We show that the CDK4/6 inhibitor PD0332991 causes a significant decrease in tumor growth in a xenotransplantation mouse model of human melanoma. shRNA knockdown of either CDK4 or CDK6 significantly reduces cell proliferation and impedes their migratory capacity in vitro, which translates into a strong inhibition of tumor growth in xenotransplantation experiments. CDK4/6 inhibition results not only in the pronounced reduction of cell proliferation but also in an impaired tumor angiogenesis. CDK6 knockdown in melanoma cell lines impairs VEGF-A expression and reduces the potential stimulation of endothelial cell growth. The knockdown of CDK4 ends in similar results. The effect is caused by changes of CDK6 localization, less CDK6 is detected on the VEGF-A promoter. Bioinformatic analysis of human melanoma patient data verifies the key role of CDK6 in tumor angiogenesis in melanoma. The results highlight the importance of the delicate balance between CDK4 and CDK6 in regulating the cell cycle and transcription.
Highlights
CDK4 and CDK6 are known as classic cell cycle kinases by forming complexes with D-type cyclins
A strong reduction in cell viability of HUVEC cells was observed when the cells were exposed to conditioned media derived from CDK4 or 6 knockdown cells (Figure 5A). These results suggest that the production and secretion of VEGF-A by melanoma cells is impaired by the stable knockdown of CDK4 and CDK6
We add a further layer of complexity; both CDK4 and CDK6 are important in melanoma and their crosstalk regulates cell proliferation, viability, migration and angiogenesis
Summary
CDK4 and CDK6 are known as classic cell cycle kinases by forming complexes with D-type cyclins. These complexes phosphorylate the Retinoblastoma protein (Rb) to regulate transition from G1 to S phase [1] [2]. Over the last years an additional function for CDK6, but not CDK4, as a transcriptional regulator in a kinase dependent and independent manner has been described [4] [5] [6] [7]. CDK6 has been shown to regulate several genes, including EGR-1, FLT-3 as well as the angiogenic factor VEGF-A. This novel function has been demonstrated to be crucial for promoting haematopoietic malignancies, including AML and ALL
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