The Role of HDAC6 in Prostate Cancer

Regulation of the stability and activity of androgen receptor by Hsp90 provides a scientific basis for current chemotherapy of prostate cancer with Hsp90 inhibitors. However, how Hsp90 activity is regulated is still not fully understood. In this current research, we have investigated the role of HDAC6 in prostate cancer development and progression through regulation of Hsp90 activity. We have found that Hsp90-ATP association, a reliable indication of Hsp90 activity, is down-regulated in HDAC6-defient cells, and have provided evidence that loss of HDAC6 in cells also down-regulates protein levels of AR and other Hsp90 client proteins, probably through increased acetylation of Hsp90 and down-modulation of co-chaperone HOP. Requirement of HDAC6 for proper Hsp90 activity and AR activity is further substantiated by the fact that HDAC6-deficient LNCaP cells have slower growth and increased cell death (observation not yet documented)in medium with charcoal-stripped serum, which can not be reversed by androgen add-back. Another unique finding from this research is the identification of B-Raf, one of the key factors in Ras-Raf-MEK-ERKsignaling axis, as a potential Hsp90 client protein. Once this finding is verified, it will have wide implications in understanding tumorigenesis as well as in cancer therapy as a whole.