Biology subjects

Elurbide, J.

Publications and source records attributed to Elurbide, J..

3 recordsLinked to original sources

bioRxiv2025

Transcriptomic profiling of epigenetic regulators and metabolic reprogramming in human cholangiocarcinoma

BackgroundEpigenetic 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). MethodWe 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. ResultsSeveral 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. ConclusionEpiGs 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.

cancer biology↗

bioRxiv2025

Histone methyl-transferase G9a inhibition boosts the efficacy of immune checkpoint inhibitors in experimental hepatocellular carcinoma

Background and AimsImmune checkpoint inhibitors (ICI) have revolutionized cancer therapy. Yet, their efficacy in hepatocellular carcinoma (HCC) remains limited, partly due to tumor-intrinsic mechanisms of immune evasion. This study focused on the identification of potential epigenetic drivers of immune resistance in HCC evaluating the therapeutic potential of targeting the histone methyltransferase G9a (EHMT2). Approach and ResultsWe analyzed G9a expression across multiple human HCC cohorts and found that elevated G9a levels were inversely correlated with the most relevant immune-related gene expression signatures predictive of ICI responsiveness. Using HCC cell lines and orthotopic models implemented in immunocompetent mice, we assessed the effects of pharmacologic inhibition of G9a with two innovative epigenetic inhibitors, CM272 and EZM8266. G9a blockade enhanced tumor cell immunogenicity by restoring IFN{gamma} responsiveness, increasing MHC-I surface expression, and promoting chemokine-mediated (CXCL10) recruitment of T cells. Mechanistically, G9a inhibition induced a viral mimicry response through derepressing endogenous retroviral elements and the accumulation of cytosolic double-stranded RNA. In vivo, G9a inhibition synergized with anti-PD-1 therapy to suppress tumor growth, significantly enhancing CD8 T cell infiltration. Notably, in a clinically-relevant post-hepatectomy HCC recurrence model, the combination therapy overcame immune resistance. ConclusionsG9a functions as a central epigenetic barrier to antitumor immunity in HCC. Pharmacologic G9a inhibition reprograms the tumor microenvironment, enhances immunogenicity, and sensitizes tumors to ICIs. These findings provide strong preclinical rationale for integrating G9a-targeted therapies with immunotherapy, particularly in perioperative settings.

pharmacology and toxicology↗

bioRxiv2023

NatB-dependent acetylation protects procaspase-8 from UBR4-mediated degradation and is required for full induction of the extrinsic apoptosis pathway

N-terminal acetyltransferase B (NatB) is a major contributor to the N-terminal acetylome and is implicated in several key cellular processes including apoptosis and proteostasis. However, the molecular mechanisms linking NatB-mediated N-terminal acetylation to apoptosis and its relationship with protein homeostasis remain elusive. In this study, we generated mouse embryonic fibroblasts (MEFs) with an inactivated catalytic subunit of NatB (Naa20-/-) to investigate the impact of NatB deficiency on apoptosis regulation. Through quantitative N-terminomics, label-free quantification, and targeted proteomics, we demonstrated that NatB does not influence the proteostasis of all its substrates. Instead, our focus on putative NatB-dependent apoptotic factors revealed that NatB-mediated acetylation serves as a protective shield against UBR4 and UBR1 Arg/N-recognin-mediated degradation. Notably, Naa20-/- MEFs exhibited reduced responsiveness to extrinsic pro-apoptotic stimuli, a phenotype that was partially reversible upon UBR4 Arg/N-recognin silencing and consequent inhibition of procaspase-8 degradation. Collectively, our results shed light on how the interplay between NatB-mediated acetylation and the Arg/N-degron pathway impacts apoptosis regulation, providing new perspectives in the field including in therapeutic interventions.

biochemistry↗