Loss of Feedback Regulation between FAM3B and Androgen Receptor Driving Prostate Cancer Progression

TMPRSS2-ERG gene fusion is one of the most frequent genetic alterations in prostate cancer (PC). Through a systematical survey of the loss of interstitial genes and patient outcomes, we nominated FAM3B as the top-ranked interstitial genes whose loss is associated with a poor prognosis. Using cultured cells, patient- and cell-line-derived xenograft models in gonad-intact or castrated host, and genetically engineered mouse models with FAM3B overexpression, knockdown, or knockout, we defined a driver role of FAM3B loss in prostate cancer progression. By performing RNA-seq analysis in two pre-clinical models with ectopic FAM3B expression or FAM3B knockdown, we identified that the androgen response pathway was commonly modulated by FAM3B in these two models. Further validation studies showed that FAM3B inhibites AR activity. FAM3B-inducible-expressing C4-2 cells and the control cells were treated with 200 ng/ml doxycycline for 48 hours. Total RNA was isolated from these cells and castration-resistant control-shRNA- or FAM3B-shRNA-expressing VCaP tumors using the TRIzol reagent. RNA integrity was assessed using an Agilent Bioanalyzer. The RNA samples from C4-2 cells were sent to Novogene for polyA-selected, 150-base paired-end RNA sequencing on an Illumina platform, and those from the VCaP tumors were sent to the Beijing Genomics Institute for polyA-selected, 100-base paired-end stranded RNA sequencing on the DNBSEQ platform.