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.
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http://dx.doi.org/10.1093/nar/gky589 | DOI Listing |
Ann Med
December 2025
Department of Breast Surgery, Second Affiliated Hospital and Cancer Institute (Provincial Key Laboratory of Tumor Microenvironment and Immunotherapy, Key Laboratory of Cancer Prevention & Intervention, National Ministry of Education), Zhejiang University School of Medicine, Hangzhou, China.
Background: Quaking (QKI) is a member of the signal transduction and activators of RNA (STAR) family, performing a crucial multifunctional regulatory role in alternative splicing, mRNA precursor processing, mRNA transport and localization, mRNA stabilization, and translation during tumour progression. Abnormal QKI expression or fusion mutations lead to aberrant RNA and protein expression, thereby promoting tumour progression. However, in many types of tumour, QKI played a role as tumour suppressor, the regulatory role of QKI in tumour progression remains ambiguous.
View Article and Find Full Text PDFEur J Immunol
December 2024
Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Tumor cell-intrinsic ubiquitin-conjugating enzyme Ubc13 promotes tumorigenesis, yet how Ubc13 in immune cell compartments regulates tumor progression remains elusive. Here, we show that myeloid-specific deletion of Ubc13 (Ubc13Lyz2) leads to accelerated transplanted lung tumor growth in mice. Compared with their littermate controls, tumor-bearing Ubc13Lyz2 mice had lower proliferation and effector function of CD8 T lymphocytes, accompanied by increased infiltration of myeloid-derived suppressor cells within the tumor microenvironment.
View Article and Find Full Text PDFClin Appl Thromb Hemost
December 2024
Department of Hematology and Transfusion sciences, School of Allied Medical Sciences, Tehran University of Medical sciences, Tehran, Iran.
Objective: DNA methylation, as an epigenetic alteration, plays an essential role in the development of atherosclerosis and venous thrombosis. E-cadherin, a tumor suppressor gene and adhesion molecule, has a crucial function in platelet aggregation and hemostasis. P16, a cell cycle regulator, is involved in venous thrombosis.
View Article and Find Full Text PDFExp Cell Res
December 2024
NHC Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, The Fourth Hospital of Harbin Medical University, Harbin, 150001, China; Department of Infectious Disease, The Fourth Hospital of Harbin Medical University, Harbin, China. Electronic address:
Lactylation is an emerging pathogenesis of hepatocellular carcinoma (HCC). However, the underlying mechanisms and biological significance remain poorly understood. The Carbonic anhydrase III (CA3) gene, previously defined as a binding protein of SQLE and involved in the NAFLD disease, has now been identified as a novel tumor suppressor in HCC.
View Article and Find Full Text PDFDrug Discov Today
December 2024
Cell Signaling and Cancer Biology Laboratory, Department of Biochemistry, Guindy Campus, University of Madras, Chennai 600025, India. Electronic address:
Salt-inducible kinases (SIKs), a group of serine/threonine kinases in the adenosine monophosphate-activated protein kinase (AMPK) family, exist in three isoforms: SIK1, SIK2 and SIK3. These kinases are crucial in various physiological processes. Emerging evidence indicates that dysregulation of SIK expression and activation significantly contributes to carcinogenesis by promoting cellular proliferation, metabolic dysregulation, metastasis and chemoresistance through the modulation of crucial signaling pathways.
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