A recent study from the Institute of Biomedicine at the University of Eastern Finland shows that the glucocorticoid receptor can both promote and inhibit prostate cancer progression, depending on the circumstances.

Glucocorticoids are steroid hormones that are also used as drugs. Owing to their strong anti-inflammatory effect, synthetic glucocorticoids are among the most prescribed group of drugs across the world, and they are also used to alleviate the side effects of cancer therapy.

The effects of glucocorticoids in the body are mediated through the glucocorticoid receptor, which binds to the DNA, altering gene transcription and thereby affecting many vital functions.

Steroid receptors also include the androgen receptor, the hyperactivity of which is the main factor contributing to the pathogenesis and progression of prostate cancer. Therefore, androgen receptor inhibition is the primary goal of drug therapy targeting prostate cancer, but prostate cancer can also become resistant to such therapies. This resistance is often facilitated by the glucocorticoid receptor, which can replace the androgen receptor and become a cancer-promoting factor itself.

These oncogenic, or cancer-promoting, effects of the glucocorticoid receptor have been studied by many research groups across the world, including by the Paakinaho Lab led by Academy Research Fellow, Docent Ville Paakinaho at the University of Eastern Finland. Previous studies have focused on the function of the glucocorticoid receptor in prostate cancer, where the activity of the androgen receptor has been inhibited by drug therapy.

“The crosstalk between the androgen and the glucocorticoid receptor in prostate cancer has, however, been overlooked in research,” Paakinaho says.

Published in Genome Research, a recent study by the Paakinaho Lab addressed this knowledge gap, utilising both genome-wide deep sequencing techniques and single-cell genomics methods.

When both the androgen and the glucocorticoid receptor were activated simultaneously, the number of binding sites for the glucocorticoid receptor in prostate cancer cells doubled. This effect was mediated by the androgen receptor, which activated regulatory regions in the DNA, allowing the glucocorticoid receptor to bind to the DNA. If the androgen receptor was not activated, the glucocorticoid receptor could not bind to these regulatory regions. The new binding sites for the glucocorticoid receptor also affected the regulation of gene transcription. The activation of both receptors synergistically affected the transcription regulation of certain genes, i.e., the combined effect of the androgen and glucocorticoid receptor was greater than their individual effects. This occurred at the level of the whole cancer cell population, as well as at the level of individual cancer cells.

Surprisingly, it was found that these synergistic effects targeted cancer suppressor genes, increasing their transcription. Bioinformatics analyses using patient data illustrated that more active transcription of these genes had a positive impact on patient survival in prostate cancer.

Thus, the glucocorticoid receptor is a double-edged sword in prostate cancer. Due to it promoting the development of drug resistance in prostate cancer, it was shown to have oncogenic effects. The results of the present study, however, indicate that the crosstalk between the androgen and the glucocorticoid receptor suppresses prostate cancer cell division and, consequently, tumour growth. In other words, the effects of glucocorticoids largely depend on androgen receptor activity. In the presence of the androgen receptor, the glucocorticoid receptor has a cancer-suppressing effect, whereas without the presence of the androgen receptor, the glucocorticoid receptor promotes cancer survival.

“It is crucial to understand the effects of this crosstalk, and how this knowledge can be leveraged in the development of better therapies,” Paakinaho says.

The study was funded by the Research Council of Finland, Sigrid Jusélius Foundation and Cancer Foundation Finland.

Research article:

Hiltunen J, Helminen L, Aaltonen N, Launonen KM, Laakso H, Malinen M, Niskanen EA, Palvimo JJ, Paakinaho V. Androgen receptor-mediated assisted loading of the glucocorticoid receptor modulates transcriptional responses in prostate cancer cells. Genome Res. 2025 Jun 2:gr.280224.124. https://doi.org/10.1101/gr.280224.124

For further information:

Transcription factor crosstalk in cancers – Paakinaho Lab website: https://uefconnect.uef.fi/en/transcription-factor-crosstalk-in-cancers-paakinaho-lab/

Related content:

https://www.uef.fi/en/article/new-insight-into-combatting-drug-resistant-prostate-cancer