Two decades ago, following a systematic screening of LOH regions on chromosome 8p22, TUSC3 has been identified as a candidate tumor suppressor gene in ovarian, prostate and pancreatic cancers. Since then, a growing body of evidence documented its clinical importance in various other types of cancers, and first initial insights into its molecular function and phenotypic effects have been gained, though the precise role of TUSC3 in different cancers remains unclear. As a part of the oligosaccharyltransferase complex, TUSC3 localizes to the endoplasmic reticulum and functions in final steps of N-glycosylation of proteins, while its loss evokes the unfolded protein response. We are still trying to figure out how this mechanistic function is reconcilable with its varied effects on cancer promotion. In this review, we focus on cancer-related effects of TUSC3 and envisage a possible role of TUSC3 beyond endoplasmic reticulum.
- MeSH
- endoplazmatické retikulum metabolismus MeSH
- epigeneze genetická MeSH
- genetické lokusy MeSH
- glykosylace MeSH
- karcinogeneze genetika metabolismus patologie MeSH
- lidé MeSH
- lidské chromozomy, pár 8 MeSH
- membránové proteiny genetika metabolismus MeSH
- nádorové buněčné linie MeSH
- nádorové supresorové proteiny genetika metabolismus MeSH
- nádory genetika metabolismus patologie MeSH
- orgánová specificita MeSH
- proliferace buněk MeSH
- regulace genové exprese u nádorů * MeSH
- signální dráha UPR MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Ovarian cancer is one of the most common malignancies in women and contributes greatly to cancer-related deaths. Tumor suppressor candidate 3 (TUSC3) is a putative tumor suppressor gene located at chromosomal region 8p22, which is often lost in epithelial cancers. Epigenetic silencing of TUSC3 has been associated with poor prognosis, and hypermethylation of its promoter provides an independent biomarker of overall and disease-free survival in ovarian cancer patients. TUSC3 is localized to the endoplasmic reticulum in an oligosaccharyl tranferase complex responsible for the N-glycosylation of proteins. However, the precise molecular role of TUSC3 in ovarian cancer remains unclear. In this study, we establish TUSC3 as a novel ovarian cancer tumor suppressor using a xenograft mouse model and demonstrate that loss of TUSC3 alters the molecular response to endoplasmic reticulum stress and induces hallmarks of the epithelial-to-mesenchymal transition in ovarian cancer cells. In summary, we have confirmed the tumor-suppressive function of TUSC3 and identified the possible mechanism driving TUSC3-deficient ovarian cancer cells toward a malignant phenotype.
- MeSH
- epitelo-mezenchymální tranzice genetika MeSH
- heterografty MeSH
- lidé MeSH
- membránové proteiny genetika MeSH
- myši inbrední NOD MeSH
- myši SCID MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádorové supresorové proteiny genetika MeSH
- nádory vaječníků genetika MeSH
- stres endoplazmatického retikula genetika MeSH
- tumor supresorové geny fyziologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Prostate cancer is the most prevalent cancer in males in developed countries. Tumor suppressor candidate 3 (TUSC3) has been identified as a putative tumor suppressor gene in prostate cancer, though its function has not been characterized. TUSC3 shares homologies with the yeast oligosaccharyltransferase (OST) complex subunit Ost3p, suggesting a role in protein glycosylation. We provide evidence that TUSC3 is part of the OST complex and affects N-linked glycosylation in mammalian cells. Loss of TUSC3 expression in DU145 and PC3 prostate cancer cell lines leads to increased proliferation, migration and invasion as well as accelerated xenograft growth in a PTEN negative background. TUSC3 downregulation also affects endoplasmic reticulum (ER) structure and stress response, which results in increased Akt signaling. Together, our findings provide first mechanistic insight in TUSC3 function in prostate carcinogenesis in general and N-glycosylation in particular.
- MeSH
- aktivace enzymů MeSH
- endoplazmatické retikulum metabolismus ultrastruktura MeSH
- genový knockdown MeSH
- glykosylace MeSH
- hexosyltransferasy chemie metabolismus MeSH
- interakční proteinové domény a motivy MeSH
- lidé MeSH
- membránové proteiny chemie nedostatek genetika metabolismus MeSH
- modely nemocí na zvířatech MeSH
- nádorové buněčné linie MeSH
- nádorové supresorové proteiny nedostatek genetika metabolismus MeSH
- nádory prostaty genetika metabolismus patologie MeSH
- pohyb buněk MeSH
- proliferace buněk MeSH
- protoonkogenní proteiny c-akt metabolismus MeSH
- regulace genové exprese u nádorů MeSH
- signální transdukce MeSH
- stres endoplazmatického retikula * genetika MeSH
- tumor burden MeSH
- vazba proteinů MeSH
- viabilita buněk genetika MeSH
- xenogenní modely - testy antitumorózní aktivity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Consequences of deregulated protein N-glycosylation on cancer pathogenesis are poorly understood. TUSC3 is a gene with a putative function in N-glycosylation, located on the short arm of chromosome 8. This is a chromosomal region of frequent genetic loss in ovarian cancer. We established recently that the expression of TUSC3 is epigenetically decreased in epithelial ovarian cancer compared to benign controls and provides prognostic information on patient survival. Therefore, we analyzed the consequences of silenced TUSC3 expression on proliferation, invasion and migration of ovarian cell lines. In addition, we performed subcellular fractionation, co-immunofluorescence and co-immunoprecipitation experiments to establish the molecular localization of TUSC3 in ovarian cancer cells. We demonstrated that TUSC3 is localized in the endoplasmic reticulum as a subunit of the oligosaccharyltransferase complex and is capable of modulation of glycosylation patterning of ovarian cancer cells. Most importantly, silencing of TUSC3 enhances proliferation and migration of ovarian cancer cells in vitro. Our observations suggest a role for N-glycosylating events in ovarian cancer pathogenesis in general, and identify TUSC3 as a tumor suppressor gene in ovarian cancer in particular.
- MeSH
- endoplazmatické retikulum enzymologie MeSH
- genový knockdown MeSH
- glykosylace MeSH
- hexosyltransferasy genetika metabolismus MeSH
- lidé MeSH
- malá interferující RNA genetika MeSH
- membránové proteiny genetika metabolismus MeSH
- nádorové buněčné linie MeSH
- nádorové supresorové proteiny genetika metabolismus MeSH
- nádory vaječníků MeSH
- podjednotky proteinů genetika metabolismus MeSH
- pohyb buněk * MeSH
- posttranslační úpravy proteinů MeSH
- proliferace buněk * MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
