Project description
Unveiling the role of epigenetics in resistance to prostate cancer therapy
Testosterone and other androgen hormones exert their function by binding to the androgen receptor (AR) that acts as a transcription factor and activates the expression of specific target genes. In prostate cancer, inhibition of AR signalling constitutes the backbone of therapy, but resistance eventually develops. The EU-funded RegARcis project is investigating the mechanism underlying this resistance by focussing on chromatin-remodelling complexes. In particular, scientists will study the switch/sucrose non-fermentable (SWI/SNF) factors implicated in nucleosome rearrangement and chromatin accessibility. The idea is to determine potential redistribution of AR binding sites that may explain therapy resistance in advanced stages of the disease.
Objective
The significance of epigenetic deregulation is a very hot topic in current prostate cancer (PC) research. New mutations have been identified in several epigenetic regulators known for their interaction with the AR. In fact, the role of chromatin remodeling factors facilitating enhancer-promoter cooperation in the formation of the AR transcriptional complex has long been demonstrated. Accordingly, the marked redistribution of AR binding sites (cistrome) during tumorigenesis is arguably the most recurrent genetic or epigenetic alterations in PC. Thus, this MCSA project aims at elucidating the role of the SWI/SNF chromatin-remodeling complex in the emergence of resistance to anti-AR signaling inhibitors. This is of utmost importance as resistance to AR signaling inhibition is arguably the principle hallmark of lethal prostate cancer. To this end, I aim at (i) investigating the SWI/SNF dependent chromatin accessibility and AR cistrome; and at (ii) assessing the actionability of SWI/SNF interacting partners in castration resistance prostate cancer (CRPC). In short, this MSCA proposal will help to define the repertoire of SWI/SNF coregulators in CRPC and to determine the extent of AR cistrome remodeling to envision new therapeutic strategies and help predict treatment response.
Fields of science
Programme(s)
Funding Scheme
MSCA-IF-EF-ST - Standard EFCoordinator
08908 L'Hospitalet De Llobregat
Spain