In my pre-doctoral study, I worked with Dr. Lirim Shemshedini (University of Toledo) on studying gene regulation by androgen receptor (AR) in prostate cancer (PCa). I have published the results on studying the cooperative role of c-Jun on AR transactivation and the roles of AR regulated SGC?1, ETV1, and MRP4 genes in PCa. In my postdoctoral training, I joined Steven Balk lab at Beth Israel Deaconess Medical Center (BIDMC)/Harvard Medical School and focused on understanding roles of AR in the lethal form of PCa (CRPC) that develops the resistance to androgen deprivation therapy (ADT). Research in the Balk lab is focused on PCa and AR, and the lab has funding from multiple sources including NIH R01 support, a Prostate Cancer SPORE, DoD Prostate Cancer program, and PCF challenge grant. My initial study is on studying the crosstalk of AR and HER signaling and then I moved to the field of studying TMPRSS2:ERG fusion gene in PCa. Using fusion positive cell lines, I have established xenograft models that clearly mimic the progression of CRPC. Studying this model led to three major findings: (1) SOX9 was identified as the major downstream effector of TMPRSS2:ERG in fusion positive PCa; (2) increased intratumoal androgen synthesis mediates tumor resistance to ADT and CYP17A1 inhibition; (3) increased AR expression in CRPC is due to relieving AR suppression of its own gene. AR plays a pivotal role in primary PCa and regains its functions in CRPC. In contrast to the wellestablished AR activation function on gene transcription, its suppression function is poorly understood. This proposal mainly focuses on elucidating the molecular mechanisms of AR mediated gene transcriptional repression. My immediate goal of 2-yrs mentored phase will be to pursue the molecular basis and clinical relevance of AR mediated its own gene expression through binding of its intron 2 site (ARBS2) and repressing the gene transcription. Several other AR-repressed gene loci that mediate expression of androgen synthetic genes (HSD17B6 and AKR1C3) will also be studied. In particularly, the repressor complex on chromatin and their actions that results in the epigenetic modifications on ARBS2 and regulates its activity will be identified. More important, any distinct mechanism that separates AR as an activator versus a repressor needs to be elucidated. These findings will also be translated into clinical therapy to enhance the activity of ARBS2 but not affect AR activated gene loci. For the long-term goal, which includes the 3-yr independence phase, the findings on AR gene loci will be extended to the whole genome of PCa cells. Taking the advantages of next generation sequencing and bioinformatics analysis on high throughput data, the global AR-mediated suppressor elements will be identified in PCa cells and their functions will also be studied. Moreover, the global roles of AR interacted repressor complex on gene transcription and on prostate cancer initiation and progression will also be studied in the phase of proposal. Current findings clearly demonstrate that we do not yet fully understand how AR functions, and that further novel mechanisms of action may contribute to its regulation of subsets of genes. As AR regulates a large number of genes involved in many cellular pathways, the potential ability to selectively target subsets of these genes has broad implications for the therapy of PCa and other diseases.
In this proposal, we are trying to elucidate the molecular mechanisms behind the novel suppression function of androgen receptor (AR) that mediates transcriptional repression on a subset of genes, which are involved in DNA synthesis and proliferation in prostate cancer. We propose that androgen deprivation therapy, which is standard for treating prostate cancer patients, may relive AR suppression of this subset of genes and result in relapse of more aggressive form of cancer, called castration resistant prostate cancer (CRPC). Therefore, distinct mechanisms of AR activation versus suppression on gene transcription make it possible to selectively augment AR transcriptional repressor function and thereby prevent or delay the emergence of CRPC.
