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SMURF2 prevents detrimental changes to chromatin, protecting human dermal fibroblasts from chromosomal instability and tumorigenesis

Abstract

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.

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Fig. 1: SMURF2 depletion accelerates cell growth and induces oncogenic phenotype/s.
Fig. 2: Depletion of SMURF2 increases cell plasticity leading to a hybrid E/M phenotype.
Fig. 3: SMURF2-deficient cells exhibit augmented DNA damage response but are compromised in damage repair.
Fig. 4: Inactivation of SMURF2 alters the epigenetic structure landscape and global chromatin compaction.
Fig. 5: Loss of SMURF2 leads to the generation of complex composite karyotypes.
Fig. 6: Accelerated cell growth and oncogenic transformation of SMURF2-deficient HDFs involves RNF20 the EZH2 signaling modules.
Fig. 7: SMURF2-depleted HDFs are highly tumorigenic in nude mice.

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Acknowledgements

We thank Sandy Boutros Suleiman for helping with some data acquisition/analysis, Gal Levy-Cohen for important administrative support, and Meir Shamay for the helpful discussions during the manuscript preparation. This work was supported by the following grants: ICRF (#00636), Marie-Curie FP-7 CIG (#612816), and Israel Cancer Association (#20160073, #20171153, and #20200007) grants awarded to MB. We are very grateful to Dayan Family Foundation for their continued support of our research.

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Manikoth Ayyathan, D., Koganti, P., Marcu-Malina, V. et al. SMURF2 prevents detrimental changes to chromatin, protecting human dermal fibroblasts from chromosomal instability and tumorigenesis. Oncogene 39, 3396–3410 (2020). https://doi.org/10.1038/s41388-020-1226-3

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