The interplay of CDK4 and CDK6 in melanoma

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.

The role of CDK6 in cancer

“…The strong correlation between CDK6 levels and enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) target gene expression in human melanoma samples, underscores the proangiogenic role of CDK6 in melanoma as EZH2 is regulated by VEGF. 75,76 CDK6 was also found to directly phosphorylate EZH2. 77 We thus postulate a dual influence of CDK6 on VEGF in melanoma.…”

Systematic exploration of different E3 ubiquitin ligases: an approach towards potent and selective CDK6 degraders

“…Cell migration is declined both in cells with shRNA-mediated CDK4/6 knockdown and CDK4/6 inhibition by palbociclib. 70,71 We employed a wound-healing assay in order to analyse the impact of PROTAC 34 on cell migration, in comparison with palbociclib and the VHL ligand VH298 (Fig. S14, ESI †).…”

Current Advances in the Treatment of BRAF-Mutant Melanoma

“…These have emerged as alternative treatment options for treating metastatic melanoma patients. Preclinical and clinical trials evaluating the efficacy of various PI3K and CDK4/6 inhibitors in combination with BRAF and MEK inhibitors are also initiated [17][18][19][20][21][22].…”