Department of Cancer Immunology, Chair of Medical Biotechnology, Poznan University of Medical Sciences, 61-701 Poznan, Poland.
Department of Cancer Diagnostics and Immunology, Greater Poland Cancer Centre, 61-866 Poznan, Poland.
Cells. 2021 Jul 29;10(8):1933. doi: 10.3390/cells10081933.
TRIM28, a multi-domain protein, is crucial in the development of mouse embryos and the maintenance of embryonic stem cells' (ESC) self-renewal potential. As the epigenetic factor modulating chromatin structure, TRIM28 regulates the expression of numerous genes and is associated with progression and poor prognosis in many types of cancer. Because of many similarities between highly dedifferentiated cancer cells and normal pluripotent stem cells, we applied human induced pluripotent stem cells (hiPSC) as a model for stemness studies. For the first time in hiPSC, we analyzed the function of individual TRIM28 domains. Here we demonstrate the essential role of a really interesting new gene (RING) domain and plant homeodomain (PHD) in regulating pluripotency maintenance and self-renewal capacity of hiPSC. Our data indicate that mutation within the RING or PHD domain leads to the loss of stem cell phenotypes and downregulation of the FGF signaling. Moreover, impairment of RING or PHD domain results in decreased proliferation and impedes embryoid body formation. In opposition to previous data indicating the impact of phosphorylation on TRIM28 function, our data suggest that TRIM28 phosphorylation does not significantly affect the pluripotency and self-renewal maintenance of hiPSC. Of note, iPSC with disrupted RING and PHD functions display downregulation of genes associated with tumor metastasis, which are considered important targets in cancer treatment. Our data suggest the potential use of RING and PHD domains of TRIM28 as targets in cancer therapy.
TRIM28 是一种多功能蛋白，在小鼠胚胎发育和维持胚胎干细胞（ESC）自我更新能力方面起着至关重要的作用。作为调节染色质结构的表观遗传因子，TRIM28 调节许多基因的表达，与许多类型癌症的进展和预后不良有关。由于高度去分化的癌细胞和正常多能干细胞之间存在许多相似之处，我们应用人诱导多能干细胞（hiPSC）作为干细胞研究的模型。我们首次在 hiPSC 中分析了单个 TRIM28 结构域的功能。在这里，我们证明了 RING 结构域和植物同源结构域（PHD）在调节 hiPSC 多能性维持和自我更新能力方面的重要作用。我们的数据表明，RING 或 PHD 结构域内的突变导致干细胞表型的丧失和 FGF 信号的下调。此外，RING 或 PHD 结构域的损伤会导致增殖减少并阻碍胚状体的形成。与先前表明磷酸化对 TRIM28 功能有影响的数据相反，我们的数据表明 TRIM28 磷酸化对 hiPSC 的多能性和自我更新维持没有显著影响。值得注意的是，具有破坏的 RING 和 PHD 功能的 iPSC 显示与肿瘤转移相关的基因下调，这些基因被认为是癌症治疗的重要靶点。我们的数据表明，TRIM28 的 RING 和 PHD 结构域可能成为癌症治疗的潜在靶点。
