Interactions Between Cell Cycle Control Proteins and the Androgen Receptor in Prostate Cancer

摘要

Cyclin Dependent Kinase 6 (CDK6) binds to and is activated by cyclin D1, and thereby enhances the transition of cells through the G1 phase of the cell cycle. We discovered that in human prostate cancer cells CDK6 binds to the androgen receptor (AR) and markedly stimulates its transcriptional activity in the presence of dihydrotestosterone (DHT). This effect of CDK6 does not require its kinase activity and is inhibited by both cyclin D1 and p16INK4a. An AR mutated at codon 877, which is found in 24% of advanced cases of prostate cancer displays exaggerated stimulation of transcriptional activity by CDK6. LNCaP prostate cancer cells engineered to overexpress CDK6 have increased expression of PSA and enhanced growth in the presence of DHT. CDK6 is present in the chromatin structure of these cells in association with the AR and the PSA gene. Furthermore, we found that primary human prostate cancers frequently displayed increased expression of CDK6. Thus, CDK6 may play an important role in the development and progression of prostate cancer.