The androgen receptor is a key transcription factor for the correct development of sexual characteristics —especially male ones— and for the physiological balance of all tissues that express this receptor. The androgen receptor is implicated in various pathologies and syndromes, such as spinal and bulbar muscular atrophy or androgen insensitivity syndrome, among others, for which there is still no definitive treatment. Considered the main factor in the initiation and progression of prostate cancer —the second most common malignant disease in men in industrialized countries—, this receptor has been the main therapeutic target for the treatment of this disease for decades.
Now, a new study describes the structural and functional effects of various mutations in the androgen receptor, and how these changes lead to the development of prostate cancer. The research has been led by Professor Eva Estébanez-Perpiñá, from the Department of Biochemistry and Molecular Biomedicine of the Faculty of Biology and the Institute of Biomedicine (IB) of the University of Barcelona (UB) —based in the Barcelona Science Park ( PCB)—in collaboration with the experts Pablo Fuentes-Prior, former head of the group at the Research Institute of the Hospital de Sant Pau (IIB Sant Pau) in Barcelona, and Álvaro Aytés, from the Bellvitge Biomedical Research Institute (IDIBELL) in Hospitalet de Llobregat and the Catalan Institute of Oncology (ICO).
In the work, whose first co-authors are Andrea Alegre and Alba Jiménez (UB-IBUB) and Adrián Martínez (ICO and IDIBELL), the team led by Professor Jaime Rubio Martínez, from the Faculty of Chemistry and the Institute of Theoretical Chemistry, also participates and Computational (IQTC) of the UB, as well as groups from the Higher Council for Scientific Research (CSIC) in Spain and the National Institute for Health and Medicine Research (INSERM) in France.
From left to right, researchers Eva Estébanez-Perpiña, Andrea Alegre-Martí, Montse Abella and Alba Jiménez-Panizo, in the UB Faculty of Biology. (Photo: UB)
Point mutations in the androgen receptor
The human androgen receptor is a key protein in the normal development and function of the prostate in response to male hormones, such as testosterone. Point mutations in the androgen receptor —specifically, the change of one amino acid for another— are one of the main mechanisms that can trigger structural and functional alterations in the receptor, which ultimately lead to the development of diseases.
The results of the work indicate that the analyzed mutations affect several functional regions of the testosterone binding domain of the androgen receptor. In particular, these are mutations that decisively alter a region of the receptor that is the target of post-transcriptional modifications (ie, modifications of the protein once it has already been produced).
These types of chemical alterations affect specific amino acids of the androgen receptor and are executed by regulatory proteins that are decisive for the correct functioning of the receptor. If this receptor regulation pathway is altered —as in the case of the presence of the mutations described by the team— its function is deregulated and can become dysfunctional and cause pathologies.
‘In our work, we have verified experimentally that these mutations deregulate a specific modification – known as arginine methylation, which is one of the types of post-transcriptional modifications – due to the structural change that these alterations produce in a functional area of the receptor. Likewise, we have been able to prove that the deregulation of the methylation of the androgen receptor also leads to relevant changes in its function within the cell”, concludes the research team.
The study is titled “A hotspot for post-translational modifications on the 1 androgen receptor dimer interface drives pathology and resistance to anti-androgens.” And it has been published in the academic journal Science Advances. (Source: UB)