BTG2 is an LXXLL-dependent co-repressor for androgen receptor transcriptional activity

The tumor suppressor gene, BTG2 has been down-regulated in prostate cancer and the ectopic expression of this gene has been shown to inhibit prostate cancer cell growth. Sequence analysis revealed that the BTG2 protein contains two leucine-rich motifs (20LxxLL24 and 92LxxLL96), which are usually found in nuclear receptor co-factors. Based on this, we postulated that there will be an association between BTG2 and AR. In this study, we discovered that BTG2 directly bound to the androgen receptor (AR) in the absence of 5α-dihydrotestosterone (DHT), and in the presence of the androgen, this interaction was increased. BTG2 bearing the mutant 20LxxLL24 motif bound to AR equally efficient as the wild-type BTG2, while BTG2 bearing the mutant 92LxxLL96 motif failed to interact with AR. Functional studies indicated that ectopic expression of BTG2 caused a significant inhibition of AR-mediated transcriptional activity and a decreased growth of prostate cancer cells. Androgen-induced promoter activation and expression of prostate-specific antigen (PSA) are significantly attenuated by BTG2. The intact 92LxxLL96 motif is required for these activities. These findings, for the first time, demonstrate that BTG2 complexes with AR via an LxxLL-dependent mechanism and may play a role in prostate cancer via modulating the AR signaling pathway.

Research highlights
► BTG2 associates with AR, androgen causes an increase of the interaction.
► BTG2 as a co-repressor inhibits the AR-mediated transcription activity.
► BTG2 inhibits the transcription activity and expression of PSA.
► An intact 92LxxLL96 motif is essential and necessary for these activities of BTG2, while the 20LxxLL24 motif is not required.
► Ectopic expression of BTG2 reduces proliferation of prostate cancer cells.