TSHZ2 is an EGF-regulated tumor suppressor that binds to the cytokinesis regulator PRC1 and inhibits metastasis.
Mary Luz UribeMaik DahlhoffRajbir Nath BatraNishanth Belugali NatarajYuya HagaDiana Drago-GarciaIlaria MarroccoArunachalam SekarSoma GhoshItay VakninSacha LebonLior KramarskiYasuo TsutsumiInpyo ChoiOscar M RuedaCarlos CaldasYosef YardenPublished in: Science signaling (2021)
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.
Keyphrases
- transcription factor
- growth factor
- cell cycle
- genome wide identification
- genome wide
- dna binding
- poor prognosis
- cell proliferation
- dna methylation
- gene expression
- end stage renal disease
- binding protein
- chronic kidney disease
- high throughput
- metabolic syndrome
- ejection fraction
- newly diagnosed
- induced apoptosis
- young adults
- copy number
- patient reported outcomes
- cell death
- skeletal muscle
- combination therapy
- cell wall