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.
Highlights
Our results suggested that TRIM28 phosphorylation does not significantly affect the mechanisms contributing to pluripotency and self-renewal maintenance in human induced pluripotent stem cells (iPSC)
We demonstrate that dysfunction of the really interesting new gene (RING) or plant homeodomain (PHD) domains and TRIM28 silencing leads to the downregulation of the Hedgehog pathway and EPCAM, implicated in stemness maintenance in iPSC
Of the numerous biological functions of TRIM28 protein, our results indicate the activity of RING and PHD domains in the transcriptional repression to be one of the main molecular mechanisms responsible for maintaining self-renewal and pluripotency
Summary
Due to self-renewal and pluripotency maintenance properties, induced pluripotent stem cells (iPSC) exhibit several features that are characteristic for cancer cells, e.g., the similar expression profile of many genes or activity of signaling pathways regulating self-renewal [1,2,3]. Epigenetic and transcriptional dysregulations in tumor cells disturb many signaling pathways responsible for maintaining the phenotype of normal stem cells, leading to progressive dedifferentiation and acquisition of stemness features [2,3]. The stemness score is the lowest in somatic cells, increased in primary tumors, and reaches the highest level in tumor metastases. This indicates that tumor progression usually involves the process of oncogenic dedifferentiation [3].
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
