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

Abstract

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.

Sci-Seq of Human Fetal Salivary Tissue Introduces Human Transcriptional Paradigms and a Novel Cell Population

“…The first, TSHZ2, was responsible for the expression of ephrin RTK EPHA4 and its ligand EFNA5 ( 144 ), among others. Overexpressing TSHZ2 in mammary glands in mice accelerated their development while preventing malignancy ( 145 ), suggesting that this factor may help to regulate the ongoing growth of the distal tip. The other transcription predicted transcription factor was EHF, an epithelial-specific Ets-family transcription factor.…”

MerTK Drives Proliferation and Metastatic Potential in Triple-Negative Breast Cancer

“…Other investigators have also reported that the overexpression of MerTK promotes cancer cell migration [39,48]. Interestingly, Uribe and colleagues reported that Axl, but not MerTK or Tyro3, correlated with the migration and invasion of colorectal cells [49]. Further, Tyro3 was identified as a direct tumor suppressor miRNA gene target that regulates the proliferation, migration, and invasion of human hepatocarcinoma cell lines [50].…”

Screening and verification of potential gene targets in the metastasis of breast cancer by bioinformatics analysis and immunohistochemistry

“…Brynychova et al[38] studied the gene expression pro le of BC patients and found poor DFS in the PRC1 overexpression group, yet could not explain paclitaxel-induced PRC1 expression (Paclitaxel toxicity) by functional analyses. Uribe et al [39] successfully inhibits mammary tumors metastasis in mice by using TSHZ2, which binds to the cytokinesis regulator PRC1. A recent study has revealed the potential role of phosphorylating PRC1 in the progression of triple-negative breast cancer [40], Whether PRC1 plays a role as an indirect marker of BC metastasis still needs further validation.…”