SUMOylation of RALY promotes vasculogenic mimicry in glioma cells via the FOXD1/DKK1 pathway

Abstract

Human malignant gliomas are the most common and aggressive primary malignant tumors of the human central nervous system. Vasculogenic mimicry (VM), which refers to the formation of a tumor blood supply system independently of endothelial cells, contributes to the malignant progression of glioma. Therefore, VM is considered a potential target for glioma therapy. Accumulated evidence indicates that alterations in SUMOylation, a reversible post-translational modification, are involved in tumorigenesis and progression. In the present study, we found that UBA2 and RALY were upregulated in glioma tissues and cell lines. Downregulation of UBA2 and RALY inhibited the migration, invasion, and VM of glioma cells. RALY can be SUMOylated by conjugation with SUMO1, which is facilitated by the overexpression of UBA2. The SUMOylation of RALY increases its stability, which in turn increases its expression as well as its promoting effect on FOXD1 mRNA. The overexpression of FOXD1 promotes DKK1 transcription by activating its promoter, thereby promoting glioma cell migration, invasion, and VM. Remarkably, the combined knockdown of UBA2, RALY, and FOXD1 resulted in the smallest tumor volumes and the longest survivals of nude mice in vivo. UBA2/RALY/FOXD1/DKK1 axis may play crucial roles in regulating VM in glioma, which may contribute to the development of potential strategies for the treatment of gliomas.

Distinctive tumorigenic significance and innovative oncology targets of SUMOylation

“…Similarly, the SUMOylation of myeloid cell leukemia 1 (MCL1) at K234 and K238 increases its protein stability through the prevention of UPS-mediated MCL1 protein degradation, leading to the proliferation of cancer cells 17 . Moreover, SUMO1-mediated SUMOylation of RNA-binding protein Raly (RALY) at K175 improves its protein stability, thereby facilitating vasculogenic mimicry in glioma cells 18 . Additionally, the noncovalent attachment of SUMO-2/3 to the SIM (236-240aa) of 5-methylcytosine (m 5 C) RNA methyltransferase NOL1/NOP2/Sun domain family member 2 (NSUN2) enhances its protein stability and induces m 5 C modification, exacerbating gastric cancer 19 .…”

O-GlcNAcylated RALY Contributes to Hepatocellular Carcinoma Cells Proliferation by Regulating USP22 mRNA Nuclear Export

“…RALY is elevated in many cancer cells and participates in tumor progression through both proliferation and aggressive biological behaviors 11 - 13 . Moreover, RALY is regulated by PTMs such as phosphorylation and SUMOylation 14 , 15 . However, the expression regulatory mechanisms of RALY are unclear and how RALY controls the progression of HCC is still largely a mystery.…”