23671

TMEFF2

CT120.2|HPP1|TENB2|TPEF|TR|TR-2;transmembrane protein with EGF-like and two follistatin-like domains 2;TMEFF2;transmembrane protein with EGF-like and two follistatin-like domains 2

cancer/testis antigen family 120, member 2|hyperplastic polyposis protein 1|tomoregulin|tomoregulin-2|transmembrane protein TENB2

2q32.3

protein-coding

HPP1 is a recently discovered gene that is epigenetically silenced in a number of tumor types, suggesting a potential role as a tumor suppressor. However, whether HPP1 has tumor suppressor activity is not clearly known. We have sought to investigate the effects of HPP1 on tumor growth and survival and to identify signaling pathways that mediate HPP1s mechanism of action. Forced expression of HPP1 into HCT116 colon cancer cell lines blocked the ability of HCT116 tumors to grown in vivo in nude mice. In cell culture, ectopic expression of HPP1 induces apoptosis and potently inhibits soft agar colony formation. HPP1 overexpression was also associated with a moderate reduction in in vitro proliferation characterized by an accumulation of cells in the G0/G1 phase of the cell cycle. Microarray analysis revealed that ectopic expression of HPP1 resulted in a dramatic upregulation of STAT1 as well as a large number of associated interferon-inducible genes. RNA interference-mediated abrogation of STAT1 reversed HPP1s antiproliferative effects. We conclude that HPP1 demonstrates tumor suppressive and pro-apoptotic activity, both in vitro and in vivo. Coupled with its inactivation in a number of tumor types, our data provides evidence to support the role of HPP1 as a tumor suppressor gene. Moreover, activation of the STAT1 pathway likely represents the principal mediator of HPP1s tumor suppressive properties.

The type I transmembrane protein with epidermal growth factor and two follistatin motifs 2 (TMEFF2) is expressed in brain and prostate and overexpressed in prostate cancer, but its role in this disease is unclear. Several studies have suggested that TMEFF2 plays a role in suppressing the growth and invasive potential of human cancer cells, whereas others suggest that the shed portion of TMEFF2, which lacks the cytoplasmic region, has a growth-promoting activity. Here we show that TMEFF2 has a dual mode of action. Ectopic expression of wild-type full-length TMEFF2 inhibits soft agar colony formation, cellular invasion, and migration and increases cellular sensitivity to apoptosis. However, expression of the ectodomain portion of TMEFF2 increases cell proliferation. Using affinity chromatography and mass spectrometry, we identify sarcosine dehydrogenase (SARDH), the enzyme that converts sarcosine to glycine, as a TMEFF2-interacting protein. Co-immunoprecipitation and immunofluorescence analysis confirms the interaction of SARDH with full-length TMEFF2. The ectodomain does not bind to SARDH. Moreover, expression of the full-length TMEFF2 but not the ectodomain results in a decreased level of sarcosine in the cells. These results suggest that the tumor suppressor activity of TMEFF2 requires the cytoplasmic/transmembrane portion of the protein and correlates with its ability to bind to SARDH and to modulate the level of sarcosine.