New insight into combatting drug-resistant prostate cancer

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A study from the University of Eastern Finland has considered the significance of the glucocorticoid receptor in drug-resistant prostate cancer. In terms of a positive outcome, the research shows the development of drug resistance could be prevented by limiting the activity of coregulator proteins.

What the research has identified is how glucocorticoids regulate vital biological processes by affecting gene encoding through a DNA-binding transcription factor, called the glucocorticoid receptor.

The activity of the glucocorticoid receptor is made extensive use of in medicine because glucocorticoids have a strong anti-inflammatory effect. Consequently synthetic glucocorticoids are one of the most prescribed drugs in the world. The medicines are used to treat inflammatory diseases, such as rheumatoid arthritis, and as adjuvant therapy for cancer patients to alleviate the side effects of cancer therapy. In blood cancer, glucocorticoids are important drugs that limit the growth of cancer cells.

Yet recent studies have shown that the glucocorticoid receptor also has an oncogenic, or cancer-promoting, effect in cancers like breast and prostate cancer. Thus, glucocorticoids help prostate cancer develop resistance to drug therapy.

According to lead researcher Docent Ville Paakinaho: “Due to these drug resistance and cancer-promoting effects, it is important to study how the glucocorticoid receptor functions on the cellular and molecular level in cancer.”

The researchers found that glucocorticoid receptor-mediated drug resistance emerges through regulatory regions, and by affecting the activity of these areas, the harmful effects of glucocorticoids in prostate cancer could be prevented.

In addition, bioinformatics analyses suggest a pioneer transcription factor, called FOXA1, presents one possible target. Inhibiting the activity of FOXA1 increases the activity of the glucocorticoid receptor – and the development of drug resistance.

The activity of the glucocorticoid receptor in regulatory regions can be influenced in drug-resistant prostate cancer through an alternative pathway. The researchers also found how coregulator proteins present an alternative target through which the glucocorticoid receptor affects the regulation of gene expression. These proteins include EP300 and CREBBP

The research appears in the journal Nucleic Acids Research. The paper is titled “Chromatin accessibility and pioneer factor FOXA1 restrict glucocorticoid receptor action in prostate cancer.”

The researchers have also been assessing ways to inhibit glucocorticoid receptor-mediated effects by inhibiting coregulator proteins.

These findings appear in the journal Cellular and Molecular Life Sciences, titled “EP300/CREBBP acetyltransferase inhibition limits steroid receptor and FOXA1 signaling in prostate cancer cells”.