SUMOylated Etv1 establishes cancer stem cells that support non-stem cancer cells tumorigenesis
Year: 2025
Type: article
Abstract: The Small Ubiquitin-like Modifier (SUMO) pathway serves as a post-translational regulatory mechanism involved in the maintenance and self-renewal of cancer stem cells/tumor-initiating cells (CSCs/TICs). In this study, we found that SUMO inhibition through genetic and pharmacologic approaches represses mammary oncogenesis and inhibits the function of CSCs. In contrast, SUMO inhibition did not affect the growth or mammosphere formation of normal mammary stem cells, suggesting SUMO-sensitive mechanisms are specific for maintaining the oncogenic CSC/TIC population. Transcriptomic analysis indicates ETS Translocation Variant 1, encoded by Etv1 gene, acts as a SUMO-sensitive transcription factor that drives mammary oncogenesis and cancer progression. Inhibition of SUMOylation resulted in a significant reduction in proliferation and colony formation in vitro and completely blocked the formation of flank xenografts in vivo. Expression of a SUMO-resistant Etv1 protein rescued in vitro growth effects, while the SUMO mimetic Etv1 protein had no effect on restoring proliferation. On the other hand, in vivo xenograft assays demonstrated that SUMO mimetic Etv1 protein efficiently induced tumor formation, whereas SUMO-resistant Etv1 protein was unable to rescue tumorigenesis. Bulk RNA-seq and ChIP-seq analyses revealed distinct gene signatures between SUMO-conjugated Etv1 in stem-like cells and SUMO-unconjugated Etv1 in proliferative, non-tumorigenic cells. Furthermore, we determined that stem-like cells could induce the proliferation of non-stem cells in tumorgenesis. Therefore, we conclude Etv1 acts as a SUMO-sensitive transcription factor that drives a stem cell phenotype necessary for mammary oncogenesis and tumorigenesis, providing potential targets for developing new therapeutic strategies.
DOI: 10.25820/etd.007957
Author: Li, Zhijie
Language: English
Topic: Cancer Cells and Metastasis
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W6889644765
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