Loss of tumor suppressor IGFBP4 drives epigenetic reprogramming in hepatic carcinogenesis

Abstract

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. ChIP-seq revealed enrichment of Ezh2/H3K27me3 at silenced loci in HBx-transgenic mouse-derived HCCs, including Igfbp4 whose down-regulation significantly correlated with EZH2 overexpression and poor survivals of HCC patients. 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. Our study unveils chromatin regulation of a novel liver tumor suppressor IGFBP4, which constitutes an AKT-EZH2 reciprocal loop in driving H3K27me3-mediated epigenetic reprogramming. Defining the aberrant chromatin landscape of HCC sheds light into the mechanistic basis of effective EZH2-targeted inhibition.

CYP27B1 Downregulation: A New Molecular Mechanism Regulating EZH2 in Ovarian Cancer Tumorigenicity

“…Therefore, the levels of AKT, p-AKT, and STAT3 were evaluated in the present study. The results indicated that EZH2 can suppress the expression and phosphorylation of AKT via a PRC-dependent mechanism, consistent with a previous study in hepatic carcinogenesis ( Lee et al, 2018 ), whereas it can promote the expression of STAT3 via a PRC2-independent mechanism and simultaneous CYP27B1 downregulation. However, the relationship between STAT3 and CYP27B1 remains to be further explored.…”

Intermittent fasting from dawn to sunset for four consecutive weeks induces anticancer serum proteome response and improves metabolic syndrome

“…PIGR, that encodes for polymeric immunoglobulin receptor 26 , was found to be downregulated in pancreatic 39 and periampullary adenocarcinoma 39 and lung cancer 40 . The upregulation of IGFBP4 (encodes for a protein that binds insulin-like growth factors I and II 26 ), was shown to function as a potent tumor suppressor in hepatocellular carcinoma and delay tumor formation in prostate cancer cells 41 , 42 . SEMA4B is involved in protein-coding 26 and encodes for a protein that inhibits tumor growth in non-small cell lung cancer 43 .…”

The Role of IGF/IGF-1R Signaling in Hepatocellular Carcinomas: Stemness-Related Properties and Drug Resistance

“…IGFBPs bind to IGF ligands with high affinity and prevent IGF-mediated IG1R activation [ 242 , 243 ]. Downregulation of IGFBPs induces cell growth, migration, and invasion and promotes HCC development [ 99 , 104 , 244 , 245 , 246 ]. An interesting study has demonstrated the tumor suppressing capacity of conditioned media derived from human fetal MSCs (CM-hfMSC) containing high levels of IGFBPs.…”