SMURF2 prevents detrimental changes to chromatin, protecting human dermal fibroblasts from chromosomal instability and tumorigenesis
| Autor: | Praveen Koganti, Andrea Emanuelli, Michael B. Blank, Dhanoop Manikoth Ayyathan, Liat Apel-Sarid, Talia Litmanovitch, Victoria Marcu-Malina, Luba Trakhtenbrot |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cancer Research Carcinogenesis Ubiquitin-Protein Ligases Mice Nude medicine.disease_cause Malignant transformation 03 medical and health sciences Mice 0302 clinical medicine Ubiquitin Chromosomal Instability Neoplasms Genetics medicine Animals Humans Enhancer of Zeste Homolog 2 Protein Epigenetics Gene Silencing Molecular Biology Tissue homeostasis biology Ubiquitination Dermis Fibroblasts Chromatin Cell biology Ubiquitin ligase 030104 developmental biology 030220 oncology & carcinogenesis Histone methyltransferase biology.protein |
| Zdroj: | Oncogene. 39(16) |
| ISSN: | 1476-5594 |
| Popis: | E3 ubiquitin ligases (E3s) play essential roles in the maintenance of tissue homeostasis under normal and stress conditions, as well as in disease states, particularly in cancer. However, the role of E3s in the initiation of human tumors is poorly understood. Previously, we reported that genetic ablation of the HECT-type E3 ubiquitin ligase Smurf2 induces carcinogenesis in mice; but whether and how these findings are pertinent to the inception of human cancer remain unknown. Here we show that SMURF2 is essential to protect human dermal fibroblasts (HDFs) from malignant transformation, and its depletion converts HDFs into tumorigenic entity. This phenomenon was associated with the radical changes in chromatin structural and epigenetic landscape, dysregulated gene expression and cell-cycle control, mesenchymal-to-epithelial transition and impaired DNA damage response. Furthermore, we show that SMURF2-mediated tumor suppression is interlinked with SMURF2’s ability to regulate the expression of two central chromatin modifiers—an E3 ubiquitin ligase RNF20 and histone methyltransferase EZH2. Silencing these factors significantly reduced the growth and transformation capabilities of SMURF2-depleted cells. Finally, we demonstrate that SMURF2-compromised HDFs are highly tumorigenic in nude mice. These findings suggest the critical role that SMURF2 plays in preventing malignant alterations, chromosomal instability and cancer. |
| Databáze: | OpenAIRE |
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