br Conflict of interest br Author contributions
Conflict of interest
Acknowledgements This work was supported by Consejo Nacional de Ciencia y Tecnología (grant number CB 220661); Programa de Apoyo a Proyectos de Investigación e Innovación Tecnológica (grant numbers IN215316 and IA204817); Programa de Apoyo a Investigación y Posgrado (grant numbers 5000-9124 and 5000-9130); Consejo Nacional de Ciencia y Tecnología–PhD grant (to S.M.G.A. and J.A.M.) and Research Assistant FQ-UNAM grant (to A. T. L. E.).
Introduction Cyclin-dependent kinases (CDKs) are serine/threonine kinases that belong to the CMGC group of kinome and their activities are regulated by cyclin binding and inhibitors from the CIP/KIP and INK4 families in response to several extra- and intracellular signals , . Deregulation of CDKs is frequently associated with human cancers , , and therefore, the development of synthetic inhibitors for therapeutic purposes has recently resulted in the approval of palbociclib (PD0332991, Ibrance®) and ribociclib (LEE011, Kisqali®) for the treatment of advanced breast cancer , , . The CDK family comprises 20 members that are responsible for the phosphorylation of substrates that are important for dpp-4 inhibitors progression and transcription. Several studies have revealed that CDKs can also mediate steroid receptor phosphorylation at multiple sites, including the androgen receptor , , . The androgen receptor (AR) is a steroid hormone receptor that plays a crucial role in the normal development of male reproductive tissues, and its high expression and/or relaxation of its regulation are strongly implicated in prostate cancer (PCa) . Androgen binding induces conformational changes of AR that influence its interactions with other proteins and DNA as well as its subcellular localization and transcriptional activity. AR is further regulated by numerous post-translational modifications (PTMs) that affect its physiological role, especially its transcriptional program. Most phosphorylation events are mediated by different kinases, including phosphorylation of serine, threonine or tyrosine residues, which are distributed along the whole AR sequence, unlike other types of PTMs , . While the proximal kinases for some phosphosites have been identified, the function of several phospho-residues and the kinases responsible for their phosphorylation are still unknown. One of the most frequently studied phosphosites, serine 81, has been shown to be phosphorylated by the CDK1, CDK5 and CDK9 kinases , , , , . Notably, overexpression of CDK1 and cyclin B have been suggested to contribute to increased AR activity in prostate cancer and its resistance to AR antagonists . Several studies have suggested that CDK1 can also cooperate with CDK7 and CDK11 to phosphorylate the other two residues of the androgen receptor, serine 515 , ,  and serine 308 , , respectively. Our study focuses on the phosphorylation of S81, the function of which was previously investigated using various approaches, including S81-phosphosite mutants, AR overexpression, inhibition, siRNA, chromatin-immunoprecipitation and cell reporters , , , , . Previous studies have demonstrated that S81 phosphorylation is required for AR nuclear translocation and association with chromatin and also regulates endogenous AR-regulated transcription in response to hormones, resulting in positive effects on cell growth.