Disruption of RING and PHD Domains of TRIM28 Evokes Differentiation in Human iPSCs

Abstract

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 Is a Novel Regulator of CD133 Expression Associated with Cancer Stem Cell Phenotype

“…TRIM28 has a role in the regulation of human iPS cells pluripotency through its RING and PHD domains [ 60 ]. It is a specific marker of glioblastoma stem-like cells and participates in their invasion [ 61 , 62 ].…”

Mining Transcriptomic Data to Uncover the Association between CBX Family Members and Cancer Stemness

“…It is well known that PRC1 and PRC2 complexes regulate stem cell pluripotency, cell fate decisions, and development and are dysregulated in many cancer types, facilitating cancer stem cell maintenance [ 20 , 21 ]. Additionally, Trim28-based gene repression machinery has a grounded place in the stem cell regulatory mechanisms [ 22 , 23 ], and recent reports demonstrate the involvement in cancer development and progression, especially by supporting the cancer stem cell population [ 24 , 25 , 26 ]. Several studies have investigated the role of Trim28- or PRC1-interacting CBX family members in cancer development and progression.…”