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

Abstract

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 5′-untranslated region (5′-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 α subunit of the translation initiation factor 2 (eIF2α) in an AR-dependent manner, paralleling the effect on TMEFF2 translation. Moreover, endoplasmic reticulum (ER) stress conditions, which promote eIF2α phosphorylation, also stimulate TMEFF2 translation. These results indicate that androgen signaling promotes eIF2α phosphorylation and subsequent translation of TMEFF2 via a mechanism that requires uORFs in the 5′-UTR of TMEFF2.

TMEFF2 Deregulation Contributes to Gastric Carcinogenesis and Indicates Poor Survival Outcome

“…Our data are consistent with previous report that TMEFF2 is initially identified as an androgen-regulated gene in prostate cancer cells and is regulated by androgens (10). Recently, another group also illustrated that androgen may regulate the translation of TMEFF2 in prostate cancer via promoting the phosphorylation level of eIF2a (28). In addition, TMEFF2 is progressively downregulated from normal gastric tissues through to precancerous tissues to gastric cancer tissues, and TMEFF2 higher expression in gastric cancer is associated with a favorable prognosis.…”

TMEFF2 and SARDH cooperate to modulate one‐carbon metabolism and invasion of prostate cancer cells

“…SARDH, GNMT, and TMEFF2 are under transcriptional control mediated by the androgen receptor (AR). In addition, translation of TMEFF2 is increased by androgens/AR signaling . These observations link AR signaling with the regulation of 1‐C metabolism and invasion.…”

Tanshinone IIA inhibits human prostate cancer cells growth by induction of endoplasmic reticulum stress in vitro and in vivo

“…Recently, a novel role for AR signaling in prostate cancer was reported. 40 AR signaling promotes eIF2a phosphorylation and as a translational regulator of TMEFF2. Tumor suppressor ability of TMEFF2 correlates with its ability to modulate sarcosine levels.…”