New research from the University of Eastern Finland highlights the importance of the glucocorticoid receptor in drug-resistant prostate cancer. Glucocorticoids play a crucial role in regulating biological processes through the glucocorticoid receptor, which is utilized in medicine for its anti-inflammatory properties. However, recent studies have shown that the glucocorticoid receptor can also have oncogenic effects in cancers like breast and prostate cancer. In prostate cancer, the glucocorticoid receptor can replace the activity of the androgen receptor, leading to drug resistance.
The Paakinaho Lab at the University of Eastern Finland conducted genome-wide deep sequencing studies to better understand how the glucocorticoid receptor functions in prostate cancer. The first study revealed that the glucocorticoid receptor can only use regulatory regions that are already active in prostate cancer cells. By affecting the activity of these regions, the harmful effects of glucocorticoids in prostate cancer could be prevented. Targeting the pioneer transcription factor FOXA1 was considered as a potential strategy to inhibit glucocorticoid receptor-mediated drug resistance.
Surprisingly, inhibiting the activity of FOXA1 actually increased the activity of the glucocorticoid receptor, leading to the development of drug resistance. Further research revealed that coregulator proteins such as EP300 and CREBBP play a crucial role in how the glucocorticoid receptor affects gene expression. Small-molecule inhibitors targeting these coregulator proteins were found to effectively prevent the activity of the glucocorticoid receptor in prostate cancer cells, inhibiting the growth of drug-resistant prostate cancer cells.
Additionally, the EP300 and CREBBP inhibitor was able to inhibit the activity of both the androgen receptor and FOXA1, without promoting glucocorticoid receptor-mediated drug resistance. By limiting the activity of FOXA1, the researchers were able to inhibit the activity of both the androgen and glucocorticoid receptors. This study suggests that targeting coregulator proteins could also be effective in untreated prostate cancer, offering new avenues for therapeutic development in this disease.
The research was funded by the Research Council of Finland, the Sigrid Jusélius Foundation, and the Cancer Foundation Finland. These findings shed light on the complex role of the glucocorticoid receptor in drug-resistant prostate cancer, and provide insights into potential therapeutic targets for inhibiting drug resistance and promoting more effective treatments for this challenging disease. Further research in this area could lead to significant advancements in prostate cancer treatment strategies.
