Transmembrane-4 Superfamily-3 (TM4SF3) was identified as a novel androgen-regulated gene in prostate cancer cells. Our data demonstrate that TM4SF3 exhibits androgen-induced repression of the mRNA but up-regulation of the protein.
The androgen positive effect on the TM4SF3 protein is of significant interest in view of the pro-cancer functions of both androgens and Tetraspanin proteins. Androgen positively regulates TM4SF3 protein stability by inhibiting its proteasome-dependent degradation. This androgen stabilization of TM4SF3 is involved in promoting prostate cancer cell invasion and migration of both androgen-dependent and androgen-independent prostate cancer cells. While confirming androgen up-regulation of the TM4SF3 protein, we observed that TM4SF3 is localized not only to the membrane, but also, surprisingly, the nuclei of prostate cancer cells. This novel nuclear localization of TM4SF3 depends on androgen-induced nuclear localization of Androgen Receptor (AR) in both androgen-dependent and androgen-independent prostate cancer cell lines. TM4SF3 interacts with AR both in prostate cancer cell types and in vitro, strongly suggesting a direct interaction. This direct interaction is required for the stabilization of not only TM4SF3, but also remarkably AR, since down-regulation of TM4SF3 resulted in reduced AR protein levels. As expected of an important AR regulator, TM4SF3 regulates androgen-dependent gene expression in and proliferation of prostate cancer cells. Importantly, a direct correlation between AR and TM4SF3 protein levels and nuclear co-localization were also observed in prostate tumors, strongly suggesting that the mutual stabilization resulting from the AR-TM4SF3 interaction is found in tumors and that this interaction is important in prostate cancer biology.
Molecular endocrinology (Baltimore, Md. ). 2015 Dec 09 [Epub ahead of print]
Meenakshi Bhansali, Jun Zhou, Lirim Shemshedini
Department of Biological Sciences, University of Toledo, Toledo, OH 43606. , Department of Biological Sciences, University of Toledo, Toledo, OH 43606. , Department of Biological Sciences, University of Toledo, Toledo, OH 43606.