SMURF2 prevents detrimental changes to chromatin, protecting human dermal fibroblasts from chromosomal instability and tumorigenesis
SMURF2 prevents detrimental changes to chromatin, protecting human dermal fibroblasts from chromosomal instability and tumorigenesis
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DOI：
10.1038/s41388-020-1226-3
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发表时间：
2020-02-26
期刊：
影响因子：
8
通讯作者：
Blank, Michael
中科院分区：
文献类型：
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作者：
Manikoth Ayyathan, Dhanoop;Koganti, Praveen;Blank, Michael
E3 泛素连接酶 (E3) 在正常和应激条件下以及疾病状态（尤其是癌症）下维持组织稳态方面发挥着重要作用。然而，人们对 E3 在人类肿瘤发生中的作用知之甚少。此前，我们报道了HECT型E3泛素连接酶Smurf2的基因消除会诱导小鼠致癌；但这些发现是否以及如何与人类癌症的发生相关仍然未知。在这里，我们证明 SMURF2 对于保护人真皮成纤维细胞 (HDF) 免遭恶性转化至关重要，并且它的缺失会将 HDF 转化为致瘤实体。这种现象与染色质结构和表观遗传景观的根本变化、基因表达和细胞周期控制失调、间充质到上皮细胞的转变以及DNA损伤反应受损有关。此外，我们发现 SMURF2 介导的肿瘤抑制与 SMURF2 调节两种中央染色质修饰剂（E3 泛素连接酶 RNF20 和组蛋白甲基转移酶 EZH2）表达的能力相互关联。沉默这些因子会显着降低 SMURF2 耗尽细胞的生长和转化能力。最后，我们证明 SMURF2 受损的 HDF 在裸鼠中具有高度致瘤性。这些发现表明 SMURF2 在预防恶性改变、染色体不稳定和癌症方面发挥着关键作用。
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.