Transcriptomic profiling of epigenetic regulators and metabolic reprogramming in human cholangiocarcinoma
Frontiers in Cell and Developmental Biology, vol. 14, pp. 1765945
Abstract
Abstract Background Epigenetic alterations play an increasingly recognized role in carcinogenesis and in the development of resistance to anticancer therapies. Epigenetic enzymes (writers and erasers) and effectors (readers) are largely influenced by the availability of metabolites grenerated through one-carbon metabolism (OCM), the tricarboxylic acid (TCA) cycle, and acetyl-CoA synthesis (ACS). In this study we examined the expression of epigenetic and metabolic genes to investigate their interplay in cholangiocarcinoma (CCA). Method We examined 257 epigenetic genes (EpiGs), 96 metabolic genes (MGs), and 189 rate-limiting enzymes (RLEs) in transcriptomic data from iCCA, eCCA, CCA organoids, and normal bile ducts, alongside prognostic signatures. CRISPR-Cas9 DepMap data evaluated the impact of EpiGs and MGs on cell viability. HuCCT-1 iCCA cells were exposed to hypoxia (1% O₂, 24 h) to assess EpiG responses. Transcriptomic deconvolution characterized EpiGs, MGs, and RLEs expression across four tumor microenvironment (TME) subtypes. Two mouse CCA models (Akt/TAZ, Akt/NICD) underwent RNA-seq, complemented by multi-omic profiling (transcriptomic, proteomic, metabolomic) in Akt/TAZ livers. Results Several EpiGs were upregulated in iCCA and eCCA, including writers ( DNMT1 , EZH2 , SUZ12 ), readers ( CBX3 , PHF20L1 , SMARCA4 ), and erasers ( HDAC1 , HDAC3 , KDM5C ). MGs in OCM, TCA, and ACS pathways were dysregulated (up: GART , IDH2 , TYMS ; down: ALDH1L1 , MAT1A , SHMT1 ). Integrated analyses identified 27 EpiGs and 8 MGs whose overexpression predicted poor survival. Subsets of EpiGs, MGs, and RLEs were linked to proliferative, high-recurrence iCCA subclasses. CRISPR screens highlighted 50 EpiGs and 23 MGs essential for CCA viability. Tumor microenvironment (TME) analyses revealed distinct immune-stromal subclasses with coherent epigenetic-metabolic signatures. In CCA cells, hypoxia induced epigenetic programs that mirrored those in CCA patients. Transcriptomic analyses in human and multi-omic analyses (transcriptomic, metabolomic, and proteomic studies) in mouse CCA livers highlighted rewiring of nucleotide, one-carbon, lipid, and mitochondrial pathways, with evidence of metabolic-epigenetic crosstalk. Conclusion EpiGs and MGs are markedly altered in both human and experimental CCA, with several changes particularly enriched in aggressive molecular subclasses associated with poor prognosis. We observed substantial rewiring of epigenetic cofactor-related MG expression in CCAs. Functional assays validated new targets among EpiGs (e.g. CBX3 , CHD4 , DEK , SMARCA4 , and TRIM28 ) and MGs ( TYMS and IDH2 ) in CCA.
Authors 21
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Navarre Institute of Health Research · Universidad de Navarra
Affiliation as printed
Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra
Instituto de Investigaciones Sanitarias de Navarra IdiSNA
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Instituto de Salud Carlos III · Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas · Universidad de Navarra
Affiliation as printed
CIBERehd, Instituto de Salud Carlos III
Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra
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Affiliation as printed
Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra
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Instituto de Salud Carlos III · Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas · Universidad de Navarra
Affiliation as printed
CIBERehd, Instituto de Salud Carlos III
Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra
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Affiliation as printed
Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra
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Affiliation as printed
Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra
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Universidad de Guadalajara · Universidad de Navarra
Affiliation as printed
Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra
Universidad de Guadalajara, Centro Universitarios de los Altos, Ciencias de la Salud
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Instituto de Salud Carlos III · Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas · Universidad de Navarra
Affiliation as printed
CIBERehd, Instituto de Salud Carlos III
Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra
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Instituto de Salud Carlos III · Navarre Institute of Health Research · Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas · Universidad de Navarra
Affiliation as printed
CIBERehd, Instituto de Salud Carlos III
Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra
Instituto de Investigaciones Sanitarias de Navarra IdiSNA
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Consejo Superior de Investigaciones Científicas · Centro Nacional de Biotecnología
Affiliation as printed
Functional Proteomics Laboratory, Centro Nacional de Biotecnología, CSIC
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Consejo Superior de Investigaciones Científicas · Centro Nacional de Biotecnología
Affiliation as printed
Functional Proteomics Laboratory, Centro Nacional de Biotecnología, CSIC
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Institute of Clinical and Experimental Medicine
Affiliation as printed
Department of Hepatogastroenterology, Institute for Clinical and Experimental Medicine
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Charles University · Institute of Clinical and Experimental Medicine · University Hospital Kralovske Vinohrady
Affiliation as printed
Clinical and Transplant Pathology Centre, Institute for Clinical and Experimental Medicine
Department of Pathology, 3rd Faculty of Medicine, Charles University and Kralovske Vinohrady University Hospital
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Charles University · Institute of Clinical and Experimental Medicine · Thomayer University Hospital
Affiliation as printed
Clinical and Transplant Pathology Centre, Institute for Clinical and Experimental Medicine
Department of Pathology and Molecular Medicine, 3rd Faculty of Medicine, Charles University and Thomayer Hospital
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Max Planck Society · Max Planck Institute of Molecular Cell Biology and Genetics
Affiliation as printed
Max Plank Institute of Molecular Cell Biology and Genetics
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Max Planck Society · Max Planck Institute of Molecular Cell Biology and Genetics
Affiliation as printed
Max Plank Institute of Molecular Cell Biology and Genetics
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Consejo Nacional de Investigaciones Científicas y Técnicas · Austral University
Affiliation as printed
Programa de Hepatología Experimental y Terapia Génica, Instituto de Investigaciones en Medicina Traslacional, Facultad de Ciencias Biomédicas, CONICET-Universidad Austral
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Max Planck Society · Max Planck Institute of Molecular Cell Biology and Genetics
Affiliation as printed
Max Plank Institute of Molecular Cell Biology and Genetics
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Instituto de Salud Carlos III · Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas · Universidad de Navarra
Affiliation as printed
CIBERehd, Instituto de Salud Carlos III
Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra
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Instituto de Salud Carlos III · Navarre Institute of Health Research · Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas · Universidad de Navarra
Affiliation as printed
CIBERehd, Instituto de Salud Carlos III
Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra
Instituto de Investigaciones Sanitarias de Navarra IdiSNA
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Instituto de Salud Carlos III · Navarre Institute of Health Research · Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas · Universidad de Navarra
Affiliation as printed
CIBERehd, Instituto de Salud Carlos III
Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra
Instituto de Investigaciones Sanitarias de Navarra IdiSNA
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