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 (GR alpha), which binds to the DNA, changing 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 (AR-alpha) inhibition is the primary goal of drug therapy targeting prostate cancer, but prostate cancer can also become resistant to such therapies.
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, or in breast cancer or ovary cancer where antiestrogens are used to antagonize estrogen receptor (ER-alpha) function. GR-alpha’s ubiquitous expression enables it to crosstalk with several other nuclear receptors in various cancers, particularly with estrogen receptor in breast cancer. An early study revealed that GR enhances ER-alpha’s chromatin binding by modulating chromatin accessibility, a process termed as the assisted loading mechanism. In this mechanism, the initiating factor (i.e., GRa) facilitates the binding of a secondary factor (i.e., ERa) to chromatin.
The key hallmarks of assisted loading include context dependency, the involvement of ATP-dependent chromatin remodeling complexes, and short-lived chromatin interactions. The latter allows both transcription factors to bind the same site without competition. Notably, in breast cancer, the GRa-ERa crosstalk has been found to play a protective role, with the loss or lack of this interaction contributing to oncogenesis. However, in endometrial cancer, the ER-GR interaction is detrimental and associated with worse outcomes for patients. This resistance is often facilitated by the glucocorticoid receptor, which can replace the androgen receptor and become a cancer-promoting factor itself. These cancer-promoting effects of the GRa have been studied by many research groups across the world, including by the Paakinaho Lab.
Published in Genome Research, a recent study by the Paakinaho Lathis team 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 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 AR and the GR 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 AR-alpha, the GR-alpha has a cancer-suppressing effect, whereas without the presence of the androgen receptor, the glucocorticoid receptor promotes cancer survival.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
Hiltunen J et al. Genome Res. 2025 Jun; in press.
Desai KB et al. Clin Cancer Res 2024; 30:2384–2392.
Fan H e tal. Mol Ther Nucleic Acids 31: 648–661.
