New insight into the fight against drug-resistant prostate cancer: New research from the University of Eastern Finland sheds light on the importance of the glucocorticoid receptor in drug-resistant prostate cancer, showing that the development of drug resistance could be prevented by limiting of the activity of co-regulator proteins.
Glucocorticoids regulate vital biological processes by affecting gene coding through a DNA-binding transcription factor, i.e. the glucocorticoid receptor. Glucocorticoid receptor activity is used extensively in medicine because glucocorticoids have a strong anti-inflammatory effect. For this reason, synthetic glucocorticoids are one of the most prescribed drugs in the world. They are used to treat inflammatory diseases, such as rheumatoid arthritis, and as adjunctive therapy for cancer patients to alleviate the side effects of cancer treatment. In blood cancer, glucocorticoids are important drugs that limit the growth of cancer cells.
However, recent studies have shown that the glucocorticoid receptor also has an oncogenic or carcinogenic effect in cancers such as breast and prostate cancer. In prostate cancer, the glucocorticoid receptor can replace the activity of the androgen receptor, which is the main oncogenic factor in this cancer, when its action is inhibited by drug therapy. Thus, glucocorticoids help prostate cancer develop resistance to drug therapy.
“Because of this drug resistance and cancer-promoting effects, it is important to study how the glucocorticoid receptor works at the cellular and molecular level in cancer,” notes Academy Researcher Docent Ville Paakinaho of the University of Eastern Finland.
The Paakinaho lab has published two recent genome-wide studies on the topic. The first, published in Nucleic Acids Research, explored how the glucocorticoid receptor replaces the androgen receptor at the molecular level.
“This study showed that the glucocorticoid receptor can only use regulatory domains that are already active in prostate cancer cells,” says PhD researcher Laura Helminen of the University of Eastern Finland.
In other words, it is through these regulatory regions that glucocorticoid receptor mediation emerges, and by affecting the activity of these regions, the deleterious effects of glucocorticoids in prostate cancer could be avoided. Bioinformatics analyzes indicated the pioneer transcription factor FOXA1 as a potential target. FOXA1 is known to have cancer-promoting properties, so the researchers hypothesized that inhibiting its activity would limit the growth of glucocorticoid receptor-mediated drug-resistant prostate cancer. Surprisingly, however, the effect was just the opposite: inhibiting FOXA1 activity further increased glucocorticoid receptor activity – and the development of drug resistance.
This is because FOXA1 was found to be involved in silencing the glucocorticoid receptor gene and this is what increased its activity when FOXA1 was inhibited.
“Research often reveals the unexpected, and that’s part of its charm,” says Paakinaho.
Glucocorticoid receptor activity in regulatory regions may, however, be affected in drug-resistant prostate cancer through an alternative pathway. Co-regulatory proteins were identified as an alternative target through which the glucocorticoid receptor affects the regulation of gene expression. These proteins include EP300 and CREBBP. Several pharmaceutical companies are developing small molecule inhibitors that target these proteins, and some are already being studied in patients.
In another study from the Paakinaho lab, researchers explored ways to inhibit the effects mediated by glucocorticoid receptors by inhibiting co-regulatory proteins. These findings were reported in Cellular and Molecular Life Sciences.
“Silencing EP300 and CREBBP proteins with a small molecule inhibitor clearly prevented glucocorticoid receptor activity in prostate cancer cells,” says project researcher Jasmin Huttunen of the University of Eastern Finland.
This allowed the growth of drug-resistant prostate cancer cells to be inhibited. In addition, the researchers found that silencing EP300 and CREBBP also effectively inhibited androgen receptor activity, especially in prostate cancer cells that have amplification of the androgen receptor gene. This amplification is found in up to half of patients with advanced prostate cancer.
Surprisingly, the EP300 and CREBBP inhibitor also inhibited FOXA1 activity while maintaining its ability to silence glucocorticoid receptor gene expression. By using EP300 and CREBBP inhibitor, it was possible to block FOXA1 activity without the development of glucocorticoid receptor-mediated drug resistance. Ultimately, inhibition of both androgen and glucocorticoid receptor activity was found to be primarily due to downregulation of FOXA1 activity. The study suggests that therapy targeting co-regulatory proteins could also be effective in untreated prostate cancer.
The studies were funded by the Research Council of Finland, the Sigrid Jusélius Foundation and the Finnish Cancer Foundation.
Paakinaho Lab Website: https://uefconnect.uef.fi/en/group/transcription-factor-crosstalk-in-cancers-paakinaho-lab/
Research articles:
Helminen L, Huttunen J, Tulonen M, Aaltonen N, Niskanen EA, Palvimo JJ, Paakinaho V. Chromatin accessibility and the pioneer factor FOXA1 limit glucocorticoid receptor activity in prostate cancer. Nucleic Acids Res. 2024 Jan 25, 52(2):625-642. https://doi.org/10.1093/nar/gkad1126
Huttunen J, Aaltonen N, Helminen L, Rilla K, Paakinaho V. EP300/CREBBP acetyltransferase inhibition limits steroid receptor and FOXA1 signaling in prostate cancer cells. Cell Mol Life Sci. 2024 Apr 2; 81(1):160. https://doi.org/10.1007/s00018-024-05209-z
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