How the structural and functional effects of mutations on androgen receptor lead to prostate cancer

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The androgen receptor is a key transcriptional factor for the proper sex development —specially in males— and the physiological balance of all the tissues that express this receptor. The androgen receptor is involved in several pathologies and syndromes, such as the spinal and bulbar muscular atrophy or androgen insensitivity syndrome, among others, for which there is no specific treatment. Regarded as the main initial and progression factor in prostate cancer —the second most common malignant disease in men in industrialized countries—, this receptor has been, for decades, the main therapeutical target for the treatment against this disease.

Now, a study published in the prestigious journal Science Advances describes the structural and functional effects of mutations on the androgen receptor, as well as how these changes lead to the development of prostate cancer. The study is led by lecturer Eva Estébanez-Perpiñá, from the Department of Biochemistry and Molecular Biomedicine of the Faculty of Biology and from the Institute of Biomedicine of the University of Barcelona (IBUB) —with headquarters at the Barcelona Science Park (PCB)—, in collaboration with the experts Pablo Fuentes-Prior, head of a research group at the Research Institute of Sant Pau (IBB Sannt Pau), and álvaro Aytés, from the Bellvitge Biomedical Research Institute (IDIBELL) and the Catalan Institute of Oncology (ICO).

The study, whose first coauthors are Andrea Alegre and Alba Jiménez (UB-IBUB) and Adrián Martínez (ICO and IDIBELL), includes the participation of the team led by lecturer Jaime Rubio Martínez, from the Faculty of Chemistry and the UB Institute of Theoretical and Computational Chemistry (IQTC), and groups from CSIC and the National Institute of Health and MedicalResearch in France (INSERM).

Point mutations in the androgen receptor

The human androgen receptor is a key protein in the development and functioning of the prostate in response to male hormones, such as testosterone. Point mutations in the androgen receptor —specifically, one aminoacid changing for another— are one of the main mechanisms than can lead to structural and functional alterations in the receptor, which result in the development of diseases.

The results of the study show that the analyzed mutations affect several functional regions of the union domain of the androgen receptor to testosterone. In particular, these are mutations that alter a region of the receptor which is the target for posttranscriptional modifications (that is, modifications in the protein once this is produced).

This type of chemical alterations affect specific amino acids of the androgen receptor and are executed by regulating proteins which are decisive for the proper functioning of the receptor. If this receptor's regulation pathway is altered —such as the case of the presence of mutations described by the team—, its function is deregulated and it can be dysfunctional and cause pathologies.

"In our study, we experimentally checked that these mutations deregulate a specific mutation, known as arginine methylation, which is one of the posttranscriptional modifications, due to the structural changes these alterations produce in a functional area of the receptor. Also, we could observe that the deregulation of the androgen receptor methylation involves relevant changes in its function within the cell", the team concludes.

Source:
Journal reference:

Alegre-Martí, A., et al. (2023). A hotspot for posttranslational modifications on the androgen receptor dimer interface drives pathology and anti-androgen resistance. Science Advances. doi.org/10.1126/sciadv.ade2175.

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