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Transcriptomic profiling of epigenetic regulators and metabolic reprogramming in human cholangiocarcinoma [HuCCT-1]

ABSTRACT: Epigenetic alterations play an increasingly recognized role in carcinogenesis and in the development of resistance to anticancer therapies. In this study, we examined the expression of epigenetic genes to investigate their interplay in cholangiocarcinoma (CCA). We examined 257 epigenetic genes (EpiGs) in transcriptomic data from HuCCT-1 iCCA cells under hypoxia (1% O₂) for 24 h. We observed that exposing the HuCCT-1 iCCA cell line to hypoxia increased the expression of key epigenetic regulators. Our results suggest that hypoxia may contribute to the activation of a shared epigenetic program associated with malignant transformation and poor prognosis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE314257 | GEO | 2026/06/25

REPOSITORIES: GEO

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Project description: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.

Project description:Background and Aims: Epithelial-mesenchymal transition (EMT) is involved in metastatic dissemination and associated with the progression of cholangiocarcinoma (CCA). Aquaporin-1 (AQP1) is a water channel expressed by cholangiocytes described to modulate cell proliferation and invasion in several cancers. However, the role of AQP1 in CCA remains unknown. Our aim was to study the function of AQP1 in CCA. Material and methods: AQP1 expression was evaluated in 39 human intrahepatic CCA (iCCA) by transcriptomic analysis. AQP1-KO in CCA cells, HucCCT1 was achieved by CRISPR/Cas9. Incucyte live-cell imaging system was used for functional studies. Next-generation sequencing (RNAseq) was used to further study the consequences of AQP1 KO. EMT and signaling pathways were evaluated by RT-qPCR, western blot, and immunostaining. In vivo experiments were performed using a xenograft CCA model. Results: AQP1 expression correlated positively with overall survival in patients with iCCA and negatively with EMT, stemness, and proliferative signatures. In vitro, RNA-seq analysis of CCA cells depleted for AQP1 showed a downregulation of epithelial markers (CDH1 and KRT19; p< 0.001) and an upregulation of mesenchymal markers (VIM and FN1; p < 0.001). In these cells, we observed a phenotypic change with induction of cell scattering, a loss of cell-cell junction protein E-cadherin, and a higher expression of vimentin and ZEB1, an EMT-inducing transcription factor. Functionally, loss of AQP1 is associated with increased cell migration and proliferation. Moreover, we found an activation of the IGF2/IGF1R/IR pathway in AQP1-depleted CCA cells. In vivo, AQP1-depleted CCA cells displayed a higher tumorigenic potential and tumor burden than control cells. Conclusion: Our data suggest that AQP1 acts as a tumor suppressor in CCA by acting both on cell proliferation and migration through an EMT process. Therefore, AQP1 might have an important role in the regulation of CCA progression.

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Transcriptomic profiling of epigenetic regulators and metabolic reprogramming in human cholangiocarcinoma [HuCCT-1]

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