Latest research from the University of Eastern Finland sheds light on the importance of the glucocorticoid receptor in drug-resistant prostate cancer, showing that the event of drug resistance could possibly be prevented by limiting the activity of coregulator proteins.

Glucocorticoids regulate vital biological processes by affecting gene encoding through a DNA-binding transcription factor, namely the glucocorticoid receptor. The activity of the glucocorticoid receptor is made extensive use of in medicine because glucocorticoids have a powerful anti-inflammatory effect. Because of this, synthetic glucocorticoids are one of the prescription drugs on this planet. They’re used to treat inflammatory diseases, similar to rheumatoid arthritis, and as adjuvant therapy for cancer patients to alleviate the negative effects of cancer therapy. In blood cancer, glucocorticoids are necessary drugs that limit the expansion of cancer cells.

Nonetheless, recent studies have shown that the glucocorticoid receptor also has an oncogenic, or cancer-promoting, effect in cancers like breast and prostate cancer. In prostate cancer, the glucocorticoid receptor can replace the activity of the androgen receptor, which is primary oncogenic consider this cancer, when its activity is inhibited by drug therapy. Thus, glucocorticoids help prostate cancer develop resistance to drug therapy.

“On account of these drug resistance and cancer-promoting effects, it’s important to check how the glucocorticoid receptor functions on the cellular and molecular level in cancer,” Academy Research Fellow, Docent Ville Paakinaho of the University of Eastern Finland notes.

The Paakinaho Lab has published two recent genome-wide deep sequencing studies on the topic. The primary, published in Nucleic Acids Research, explored how the glucocorticoid receptor replaces the androgen receptor on the molecular level.

This study showed that the glucocorticoid receptor can only use regulatory regions which might be already energetic in prostate cancer cells.”

Laura Helminen, Doctoral Researcher, University of Eastern Finland

In other words, glucocorticoid receptor-mediated drug resistance emerges through these regulatory regions, and by affecting the activity of those areas, the harmful effects of glucocorticoids in prostate cancer could possibly be prevented. Bioinformatics analyses indicated the pioneer transcription factor FOXA1 as one possible goal. FOXA1 is thought to have cancer-promoting properties, which is why the researchers assumed that inhibiting its activity would limit the event of glucocorticoid receptor-mediated drug-resistant prostate cancer. Surprisingly nonetheless, the effect was exactly the alternative: inhibiting the activity of FOXA1 further increased the activity of the glucocorticoid receptor – and the event of drug resistance.

It is because FOXA1 was found to be involved within the silencing of the glucocorticoid receptor gene, and that is what increased its activity when FOXA1 was inhibited.

“Research often reveals the unexpected, and that is a part of its charm,” Paakinaho says.

The activity of the glucocorticoid receptor in regulatory regions can, nonetheless, be influenced in drug-resistant prostate cancer through an alternate pathway. Coregulator proteins were identified instead goal through which the glucocorticoid receptor affects the regulation of gene expression. These proteins include EP300 and CREBBP. Several pharmaceutical firms are developing small-molecule inhibitors targeting these proteins, and a few are already being studied in patients.

In one other study by the Paakinaho Lab, the researchers explored ways to inhibit glucocorticoid receptor-mediated effects by inhibiting coregulator proteins. These findings were reported in Cellular and Molecular Life Sciences.

“Silencing the EP300 and CREBBP proteins with a small-molecule inhibitor clearly prevented the activity of the glucocorticoid receptor in prostate cancer cells,” Project Researcher Jasmin Huttunen of the University of Eastern Finland says.

This allowed the expansion of drug-resistant prostate cancer cells to be inhibited. Moreover, the researchers found that silencing EP300 and CREBBP also effectively inhibited the activity of the androgen receptor especially in prostate cancer cells which have an amplification of the androgen receptor gene. This amplification is present in as much as half of patients with advanced prostate cancer.

Surprisingly, the EP300 and CREBBP inhibitor also inhibited the activity of FOXA1, while still preserving its ability to silence the expression of the glucocorticoid receptor gene. Through the use of the EP300 and CREBBP inhibitor, it was possible to dam the activity of FOXA1 without the event of glucocorticoid receptor-mediated drug resistance. Ultimately, inhibiting the activity of each the androgen and the glucocorticoid receptor was found to be primarily because of the limitation of FOXA1 activity. The study suggests that treatment targeting coregulator proteins may be effective in untreated prostate cancer.

The studies were funded by the Research Council of Finland, the Sigrid Jusélius Foundation, and the Cancer Foundation Finland.