SUMOylation of IGF2BP2 promotes vasculogenic mimicry of glioma via regulating OIP5-AS1/miR-495-3p axis

Abstract

Rationale: Glioma is the most common primary malignant tumor of human central nervous system, and its rich vascular characteristics make anti-angiogenic therapy become a therapeutic hotspot. However, the existence of glioma VM makes the anti-angiogenic therapy ineffective. SUMOylation is a post-translational modification that affects cell tumorigenicity by regulating the expression and activity of substrate proteins. Methods: The binding and modification of IGF2BP2 and SUMO1 were identified using Ni 2+ -NTA agarose bead pull-down assays, CO-IP and western blot; and in vitro SUMOylation assays combined with immunoprecipitation and immunofluorescence staining were performed to explore the detail affects and regulations of the SUMOylation on IGF2BP2. RT-PCR and western blot were used to detect the expression levels of IGF2BP2, OIP5-AS1, and miR-495-3p in glioma tissues and cell lines. CCK-8 assays, cell transwell assays, and three-dimensional cell culture methods were used for evaluating the function of IGF2BP2, OIP5-AS1, miR-495-3p, HIF1A and MMP14 in biological behaviors of glioma cells. Meantime, RIP and luciferase reporter assays were used for inquiring into the interactions among IGF2BP2, OIP5-AS1, miR-495-3p, HIF1A and MMP14. Eventually, the tumor xenografts in nude mice further as certained the effects of IGF2BP2 SUMOylation on glioma cells. Results: This study proved that IGF2BP2 mainly binds to SUMO1 and was SUMOylated at the lysine residues K497, K505 and K509 sites, which can be reduced by SENP1. SUMOylation increased IGF2BP2 protein expression and blocked its degradation through ubiquitin-proteasome pathway, thereby increasing its stability. The expressions of IGF2BP2 and OIP5-AS1 were up-regulated and the expression of miR-495-3p was down-regulated in both glioma tissues and cells. IGF2BP2 enhances the stability of OIP5-AS1, thereby increasing the binding of OIP5-AS1 to miR-495-3p, weakening the binding of miR-495-3p to the 3'UTR of HIF1A and MMP14 mRNA, and ultimately promoting the formation of VM in glioma. Conclusions: This study first revealed that SUMOylation of IGF2BP2 regulated OIP5-AS1/miR-495-3p axis to promote VM formation in glioma cells and xenografts growth in nude mice, providing a new idea for molecular targeted therapy of glioma.

APOLLO: An accurate and independently validated prediction model of lower-grade gliomas overall survival and a comparative study of model performance

“…Further, we briefly summarized the biological functions of these transcriptional biomarkers in APOLLO. For the genes with significant main effects, the genetic variants of CHIC2 are found in brain tumor tissues, 37 and ITGAV 38 is a prognostic factor of gliomas; PLCG1 and IGF2BP2 are related to SUMOylation and m6A methylation, and involved in the immune responses, occurrence and development of gliomas; 39 , 40 , 41 MSN is an active biomarker for glioma immune regulation and a drug target. 42 For the pairs of genes with significant interactions, PRF1 is strongly associated with anti-CTLA-4 or anti-PD-L1 immunotherapy, and is related to immune cell activities and survival of gliomas.…”

m6A regulator–mediated RNA methylation modification patterns and immune microenvironment infiltration characterization in patients with intracranial aneurysms

“…Deng et al showed that IGF2BP2 can bind to mRNA in an m6A-dependent manner and thus has the potential to become a new diagnostic and therapeutic target for patients with Alzheimer's disease (52). It has also been shown that SUMOylation of IGF2BP2 promotes angiogenic mimicry in gliomas by regulating the OIP5-AS1/miR-495-3p axis (53). In addition, YTHDF3, ALKBH5, RBM15B, LRPPRC, and ELAVL1 are all involved in m6A RNA methylation modifications (54).…”

Induction of lncRNA NORAD accounts for hypoxia-induced chemoresistance and vasculogenic mimicry in colorectal cancer by sponging the miR-495-3p/ hypoxia-inducible factor-1α (HIF-1α)

“…More interestingly, previous evidence supported miR-495 as a chemoradiotherapy-sensitive gene in CRC patients [ 21 ]. Additionally, miR-495-3p is also involved in VM formation in glioma [ 38 ]. Noticeably, the present data highlighted that blockage of miR-495-3p expression overturned the NORAD loss-mediated inhibition of HIF-1α-EMT signaling, and subsequent VM formation and 5-FU resistance in CRC cells under hypoxic conditions.…”