Effect of depletion of CDK4 on gene expression of MCF-7 breast cance cells
CDK4/6 inhibitors act as a cytostatic by targeting CDK4/6-cyclin D, and have achieved great success in hormone receptor-positive breast cancer treatment. Beyond cell cycle signaling pathway, recent research on non-cell cycle related functions of CDK4/6 has been blooming. Insights in this field may expand the therapeutic benefits of CDK4/6 inhibitors. Here, we attempt to explore the effects of CDK4/6 inhibitors on breast cancer from the perspective of epigenetic modifications, especially histone modifications, through high-throughput proteomic and genomics approaches. We reveal that inhibition of CDK4 directly suppresses phosphorylation of p300, an acetyltransferase, stimulates its ubiquitin degradation, and down-regulates the histone H3K27ac. Then, p300-mediated transcriptionally inhibition of BRCA1 and enrichment of breast cancer stem cells (BCSC) gene signatures lead to the increase of the proportion of ALDH1+ breast CSCs in ER+ breast cancer after long treatment with CDK4/6 inhibitors in vitro and in vivo. our results reveal a novel phosphorylation substrate of CDK4/cyclin D complex, and offer an unrecognized side effect of CDK4/6 inhibitors, inducing stem cell properties in ER+ breast cancer. Overall design: We established MCF-7 cell line in which target gene has been knocked down by siRNA.