ArticleCancer genomics & proteomics
Transcriptomic Profiling Identifies Higher DOT1L Expression as a Candidate Biomarker for a Positive Response to Gemcitabine in Cholangiocarcinoma.
Article in Cancer genomics & proteomics. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
BACKGROUND/
aimCholangiocarcinoma (CCA) has a poor prognosis, partly due to late diagnosis and limited efficacy of systemic therapies. Gemcitabine remains a commonly used chemotherapeutic agent for CCA; however, the clinical response is heterogeneous, and predictive biomarkers are lacking. Although epigenetic regulators have been implicated in gemcitabine sensitivity in other malignancies, their relevance in CCA has not been explored systematically. This study aimed to identify epigenetic candidates associated with the gemcitabine response in CCA and to validate their functional role. MATERIALS AND
methodsRNA sequencing was performed on 24 paired non-tumor and tumor bile duct tissues. Differential expression and enrichment analyses were conducted to identify pathways and epigenetic regulators associated with the gemcitabine response. DOT1L was prioritized and experimentally validated in a human CCA cell line (SSP25) using assays for cell proliferation, sphere formation, cell cycle distribution, and EdU incorporation. Mechanistic readouts included cyclin-dependent kinase 2 (CDK2) phosphorylation and caspase-3 cleavage. DOT1L protein expression was examined in patient specimens via immunohistochemistry.
resultsTranscriptomic profiling identified DOT1L as the only epigenetic regulator consistently enriched in tumors from gemcitabine responders. The gene ontology (GO) analysis revealed reduced chromatin-remodeling programs in non-responders, consistent with higher DOT1L expression in responders. In SSP25 cells, DOT1L overexpression increased gemcitabine sensitivity, accompanied by S-phase arrest and enhanced apoptosis, as evidenced by increased CDK2 phosphorylation and caspase-3 cleavage. Immunohistochemistry showed higher DOT1L expression in clinical specimens from gemcitabine responders than in those from non-responders.
conclusionOur integrated transcriptomic and functional analyses support DOT1L as a clinically relevant epigenetic factor associated with the response of CCA to gemcitabine and suggest a mechanistic link involving S-phase regulation and apoptosis. DOT1L may serve as a candidate biomarker and a potential target to improve gemcitabine efficacy in CCA.
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