Androgen Signaling Promotes Translation of TMEFF2 in Prostate Cancer Cells via Phosphorylation of the α Subunit of the Translation Initiation Factor 2

The type I transmembrane protein with epidermal growth factor and two follistatin motifs 2 (TMEFF2), is expressed mainly in brain and prostate. Expression of TMEFF2 is deregulated in prostate cancer, suggesting a role in this disease, but the molecular mechanism(s) involved in this effect are not clear. Although androgens promote tmeff2 transcription, androgen delivery to castrated animals carrying CWR22 xenografts increases TMEFF2 protein levels in the absence of mRNA changes, suggesting that TMEFF2 may also be post-transcriptionally regulated. Here we show that translation of TMEFF2 is regulated by androgens. Addition of physiological concentrations of dihydrotestosterone (DHT) to prostate cancer cell lines increases translation of endogenous TMEFF2 or transfected TMEFF2-Luciferase fusions, and this effect requires the presence of upstream open reading frames (uORFs) in the 59-untranslated region (59-UTR) of TMEFF2. Using chemical and siRNA inhibition of the androgen receptor (AR), we show that the androgen effect on TMEFF2 translation is mediated by the AR. Importantly, DHT also promotes phosphorylation of the alpha subunit of the translation initiation factor 2 (eIF2 alpha) in an AR-dependent manner, paralleling the effect on TMEFF2 translation. Moreover, endoplasmic reticulum (ER) stress conditions, which promote eIF2 alpha phosphorylation, also stimulate TMEFF2 translation. These results indicate that androgen signaling promotes eIF2 alpha phosphorylation and subsequent translation of TMEFF2 via a mechanism that requires uORFs in the 59-UTR of TMEFF2.