Endocrine Abstracts

Castrate Resistant Prostate Cancer (CRPC) is the inevitable outcome of hormone treatment for advanced disease. Although no longer dependent on high levels of androgens, the androgen receptor (AR) remains active and there is evidence that other nuclear receptors (NRs) can drive CRPC progression and/or therapy resistance. NRs share a repertoire of essential coregulators: proteins possessing the ability to aid or repress NR action and have been proposed as a potential mechanism for driving this inevitably lethal disease. Using publically available datasets we have found distinct patterns of coregulator expression between CRPC and hormone naïve disease. Importantly, we could identify a group of coregulators that were consistently differentially expressed across all cohorts. These could be further categorise into distinct function clusters or pathways.

One such comprises TRIpartite Motif (TRIM) proteins TRIM24, TRIM28, and TRIM33. These form a unique subgroup of the larger TRIM family, in that only these three have Bromo-domains. Co-immunoprecipitation assay for endogenous proteins reveals that these proteins interact with each other and AR. Using ChIP-seq data we identified AR regulated genes which are also potentially TRIM24 and TRIM28 targeted. Using ChIP and RT-qPCR we were able to validate TRIM24 and TRIM28 binding independently or concurrently to AR target genes VEGFA, SLC45A3, CXCR7. Silencing TRIMs can alter androgen regulation of such genes, and was also able to reduce proliferation and response to androgen in AR-expressing prostate cancer cells. Intriguingly in one such cell line (22RV1), silencing individual TRIMs made no difference to anti-androgen response, but simultaneous silencing resensitized cells to the antiandrogen enzalutamide. Furthermore their expression in TCGA data sets could be used together to predict biochemical relapse. Our data suggest that TRIM24 and TRIM28 proteins interact, in gene specific manners, to regulate AR activity and may provide a potential target to increase effectiveness of anti-androgen therapy.