CDK4/6 inhibitors modulate the ubiquitin proteosomal pathway by suppression of the ubiquitin conjugating enzymes UBE2C/S/T

Despite significant improvement in therapeutic development in the past decades, breast cancer remains a formidable cause of death for women worldwide. The hormone positive subtype (HR(+)) (also known as luminal type) is the most prevalant category of breast cancer, comprising ~70% of patients. The clinical success of the three CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib has revolutionzied the treatment of choice for metastatic HR(+) breast cancer. Accumulating evidence demonstrate that the properties of CDK4/6 inhibitors extend beyond inhibition of the cell cycle, including modulation of immune function , sensitizing PI3K inhibitors, metabolism reprogramming , kinome rewiring, modulation of the proteosome, and many others. The ubiquitin–proteasome pathway (UPP) is a crucial cellular proteolytic system that maintains the homeostasis and turnover of proteins. By transcriptional profiling of the HR(+) breast cancer cell lines treated with the three CDK4/6 inhibitors, we have uncovered a novel mechanism that demonstrate the CDK4/6 inhibitors suppress the expression of three ubiquitin conjugating enzymes UBE2C, UBE2S, UBE2T. These three E2 enzymes modulate a number of E3 ubiquitin ligases, including the APC/C complex which plays a role in G1/S progression. Our study provide a novel link between CDK4/6 inhibitor and UPP which could have important implications in cancer biology. The hormone (+) breast cancer cell lines MCF-7, T47D were treated with the CDK4/6 inhibitors palbociclib for 5 days and subject to RNA-sequencing to profile the transcriptomic changes.