TSHZ2 is an EGF-regulated tumor suppressor that binds to the cytokinesis regulator PRC1 and inhibits metastasis

Menée à l'aide de lignées cellulaires, d'une xénogreffe sur un modèle murin et de données portant sur 1 980 patientes atteintes d'un cancer du sein, cette étude démontre que le facteur de transcription TSHZ2 est un suppresseur de tumeur qui se lie à la protéine PRC1 et inhibe le processus métastatique

Résumé en anglais

Rapid induction or repression of gene expression in response to mitogens, such as the growth factor EGF, has been intensively investigated. Uribe et al. examined genes they called delayed down-regulated genes (DDGs) that are repressed hours after EGF stimulation in mammary cells. One DDG encoded the transcription factor TSHZ2, which interacted with and inhibited mitotic proteins through transcriptional and possibly posttranslational mechanisms. TSHZ2 promoted mammary gland development and inhibited mammary tumor growth and progression in mice. In breast tumors from patients, decreased TSHZ2 expression often correlated with increased methylation of its promoter. The findings provide insight into the role of TSHZ2 as a mitotic regulator.Unlike early transcriptional responses to mitogens, later events are less well-characterized. Here, we identified delayed down-regulated genes (DDGs) in mammary cells after prolonged treatment with epidermal growth factor (EGF). The expression of these DDGs was low in mammary tumors and correlated with prognosis. The proteins encoded by several DDGs directly bind to and inactivate oncoproteins and might therefore act as tumor suppressors. The transcription factor teashirt zinc finger homeobox 2 (TSHZ2) is encoded by a DDG, and we found that overexpression of TSHZ2 inhibited tumor growth and metastasis and accelerated mammary gland development in mice. Although the gene TSHZ2 localizes to a locus (20q13.2) that is frequently amplified in breast cancer, we found that hypermethylation of its promoter correlated with down-regulation of TSHZ2 expression in patients. Yeast two-hybrid screens and protein-fragment complementation assays in mammalian cells indicated that TSHZ2 nucleated a multiprotein complex containing PRC1/Ase1, cyclin B1, and additional proteins that regulate cytokinesis. TSHZ2 increased the inhibitory phosphorylation of PRC1, a key driver of mitosis, mediated by cyclin-dependent kinases. Furthermore, similar to the tumor suppressive transcription factor p53, TSHZ2 inhibited transcription from the PRC1 promoter. By recognizing DDGs as a distinct group in the transcriptional response to EGF, our findings uncover a group of tumor suppressors and reveal a role for TSHZ2 in cell cycle regulation.