Loss of tumor suppressor IGFBP4 drives epigenetic reprogramming in hepatic carcinogenesis.


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.





Published Version (Please cite this version)


Publication Info

Lee, Ying-Ying, Myth Ts Mok, Wei Kang, Weiqin Yang, Wenshu Tang, Feng Wu, Liangliang Xu, Mingfei Yan, et al. (2018). Loss of tumor suppressor IGFBP4 drives epigenetic reprogramming in hepatic carcinogenesis. Nucleic acids research, 46(17). pp. 8832–8847. 10.1093/nar/gky589 Retrieved from https://hdl.handle.net/10161/20050.

This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.



Qianben Wang

Professor of Pathology

Dr. Wang's laboratory is primarily focused on understanding the transcriptional and epigenetic mechanisms that drive the progression of hormone-dependent cancers. Additionally, they investigate the role of host proteases in coronavirus infection. Their recent studies aim to combine CRISPR/Cas13 technologies with nanotechnology to target undruggable transcription factors in cancers and host proteases for controlling infections caused by SARS-CoV-2 and related coronaviruses.

Unless otherwise indicated, scholarly articles published by Duke faculty members are made available here with a CC-BY-NC (Creative Commons Attribution Non-Commercial) license, as enabled by the Duke Open Access Policy. If you wish to use the materials in ways not already permitted under CC-BY-NC, please consult the copyright owner. Other materials are made available here through the author’s grant of a non-exclusive license to make their work openly accessible.