IGFBP4

Case Study 1: Ying-Ying Lee, 2018

Genomic sequencing of hepatocellular carcinoma (HCC) uncovers a paucity of actionable mutations, underscoring the necessity to exploit epigenetic vulnerabilities for therapeutics. In HCC, EZH2-mediated H3K27me3 represents a major oncogenic chromatin modification, but how it modulates the therapeutic vulnerability of signaling pathways remains unknown. Here, we show EZH2 acts antagonistically to AKT signaling in maintaining H3K27 methylome through epigenetic silencing of IGFBP4. Functional characterizations demonstrated potent growth- and invasion-suppressive functions of IGFBP4, which was associated with transcriptomic alterations leading to deregulation of multiple signaling pathways. Mechanistically, IGFBP4 stimulated AKT/EZH2 phosphorylation to abrogate H3K27me3-mediated silencing, forming a reciprocal feedback loop that suppressed core transcription factor networks (FOXA1/HNF1A/HNF4A/KLF9/NR1H4) for normal liver homeostasis. Consequently, the in vivo tumorigenicity of IGFBP4-silenced HCC cells was vulnerable to pharmacological inhibition of EZH2, but not AKT.

Fig1. Western blot analysis of HepG2 and Huh7 cells transiently transfected with empty vector or IGFBP4-expression plasmid.

Fig2. Scatter plots showing the global gene expression in HepG2 cells with or without IGFBP4 re-expression.

Case Study 2: Wenhu Chen, 2023

Breast cancer (BC) is the most frequent malignant tumor in women worldwide with exceptionally high morbidity. The RNA-binding protein MEX3A plays a crucial role in genesis and progression of multiple cancers. The researchers attempted to explore its clinicopathological and functional significance in BC in which MEX3A is expressed. MEX3A and IGFBP4 profile data of BC patients were downloaded from TCGA and GEO database. Western Blot, CCK-8, EdU, colony formation and flow cytometry were performed to investigate the role of MEX3A and IGFBP4 in BC cell proliferation, invasion and cell cycle in vitro. The interactions among MEX3A and IGFBP4 were measured by RNA pull-down and RNA immunoprecipitation. The expression of IGFBP4 was significantly negatively correlated with MEX3A in BC tissues. Mechanistic investigation showed that MEX3A binds to IGFBP4 mRNA in BC cells, decreasing IGFBP4 mRNA levels, which further activated the PI3K/AKT and other downstream signaling pathways implicated cell cycle progression and cell migration.

Fig3. RNA pull-down assay and western blot analysis of the specific association of MEX3A proteins with IGFBP4 revealed that biotinylated IGFBP4 could bind to MEX3A.

Fig4. Western blot shows protein expression of PI3K/AKT, MAPK pathway and cell cycle in BC cells co-transfected with si-MEX3A and si-IGFBP4.

Fig1. The mechanistic pathway of IGFBP4/AKT/EZH2 epigenetic circuitry. (Ying-Ying Lee, 2018)

Fig2. Regulation of IGF bioactivity by the IGFBP-4/PAPP-A/STC axis. (Rikke Hjortebjerg, 2018)

IGFBP4 involved in several pathways and played different roles in them. We selected most pathways IGFBP4 participated on our site, such as Metabolism of proteins, Myometrial Relaxation and Contraction Pathways, Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs), which may be useful for your reference. Also, other proteins which involved in the same pathway with IGFBP4 were listed below. Creative BioMart supplied nearly all the proteins listed, you can search them on our site.

IGFBP4 has several biochemical functions, for example, insulin-like growth factor I binding, insulin-like growth factor II binding. Some of the functions are cooperated with other proteins, some of the functions could acted by IGFBP4 itself. We selected most functions IGFBP4 had, and list some proteins which have the same functions with IGFBP4. You can find most of the proteins on our site.

IGFBP4 has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with IGFBP4 here. Most of them are supplied by our site. Hope this information will be useful for your research of IGFBP4.

SUV39H1; KDM1A; q81l39_bacan