Investigating the androgen-based hormonal regulation of Erad and it's role in prostate cancer progression

In eukaryotic cells synthesis of one third of total proteome occurs in the Endoplasmic Reticulum (ER). The folding of of newly synthesized proteins to mature forms is controlled by the "protein quality control" mechanism, which is tightly regulated in the ER. The proteins that can not reach the final form due to mutations, genotoxic effects or cellular stress are firstly incorporated into the repetitive folding process in order to prevent arrival to their functional site. Nonetheless, proteins that can not fold properly, are transported to 26S proteasome for degradation via recognition and ubiqitination by a mechanism known as as ER-associated protein degradation (ERAD) pathway. It is also known that ERAD regulates endogenous levels of many normal proteins under physiological conditions. Many key molecules such as channel proteins, chaperones, E1-E2-E3 enzymes involved in ubiquitination, motor proteins responsible for retrotranscription, and cofactors accompanying the process are in sync with each other In ERAD. It is known that ubiquitin ligases and their dynamic ERAD complexes, unfolded protein response (UPR) and endogenous ERAD inhibitor protein play a role in the regulation of ERAD. The ERAD inhibitor protein SVIP expression has been reported to decrease after androgen administration in a LONG-SAGE library screening examined the androgen-mediated changes in gene expression, however no detailed information on regulation has been reported. From this, we hypothesized that ERAD could be regulated by androgens and aimed to examine ERAD-mediated regulation of androgens in our project. Within this PhD thesis, the regulation of ERAD through androgens was characterized and it was determined that the regulation of ERAD is mediated by direct regulation of the androgen receptor (AR). It is known that AR signalization plays an important role in the development of prostate cancer. The roles of ERAD members in prostate cancer cells were examined by functional tests. ERAD has been shown to have an important role in regulation of proliferative, migratory and malignant transformation abilities of prostate cancer cells. The data, we have revealed, suggests that ERAD may be a mechanism to be targeted in the development of prostate cancer and in the treatment of prostate cancer. In conclusion, the results of our project will shed light on both literature and the formation of new projects and also the design of potential therapeutic approaches. Key words: ERAD; Androgen; Prostate cancer; LNCa