OR22-04 The Oncogenic Action Of Glucocorticoid Receptor In Prostate Cancer

Abstract

Abstract Disclosure: V. Paakinaho: None. Steroid receptors, such as androgen (AR), and glucocorticoid receptor (GR), are hormone-controlled transcription factors (TFs) that regulate transcription in multiple central cellular systems. The action of steroid receptors has a major role in the development and progression diseases, especially endocrine-related cancers, such as prostate cancer. Since AR is the key oncogenic TF driving the development and progression of prostate cancer, the receptor is the major precision drug target in the disease. Therefore, antiandrogen treatment, i.e., the inhibition of AR activity, is a common form of cancer therapy. Despite the initial effectiveness of the therapy, antiandrogen resistance often occurs and there is no curable treatment in many cases. In contrast to AR, GR has been thought to possess tumor suppressive properties in therapy-naïve prostate cancer. Nonetheless, GR can hijack the oncogenic role of AR in prostate cancer by replacing the antiandrogen inactivated AR thus mediating antiandrogen-resistance and becoming the driver of the disease. Yet, the genome-wide effects of GR in prostate cancer have largely remained elusive. The tumor suppressive versus the oncogenic consequences of GR activation are important to acknowledge since prostate cancer patients regularly receive glucocorticoids to reduce inflammation and alleviate therapy-related side effects. To unveil these issues, we integrated ChIP-seq, RNA-seq, ATAC-seq data and uncover several pivotal features of GR action in prostate cancer cells. We detected that the replacement of AR by GR in antiandrogen-exposed prostate cancer cells occurs almost exclusively at pre-accessible chromatin sites displaying the occupancy of FOXA1. Counterintuitively to the classical pioneer factor model, the silencing of FOXA1 potentiated the chromatin binding and transcriptional activity of GR. This was attributed to FOXA1-mediated repression of the NR3C1 (gene encoding GR) expression via the corepressor TLE3. Additionally, we discovered that the chromatin binding of GR as well as transcriptional regulation by the receptor differs between different prostate cancer subtypes. Moreover, GR activity in normal prostate cells diverges drastically from that of the cancer cells. In sum, our data highlight the impact FOXA1 harbors in GR-mediated antiandrogen-resistant prostate cancer. Furthermore, the distinct GR transcriptional activity in prostate cancer subtypes could potentially be used to determine if glucocorticoid exposure possess potential harm for the prostate cancer patient. Presentation: Saturday, June 17, 2023