AI Insight
This study identifies Y-box-binding protein 1 (YB-1) as a key driver of cisplatin resistance in intrahepatic cholangiocarcinoma through single-cell RNA sequencing and functional experiments. The researchers found that cisplatin treatment triggers YB-1 to move into the cell nucleus where it activates ABCB1, a protein that pumps chemotherapy drugs out of cancer cells. This activation requires degradation of DNA methyltransferases (DNMT1 and DNMT3B) through an m6A-dependent RNA decay pathway, which removes methylation marks that normally silence the ABCB1 gene.
Why it matters
The findings reveal a molecular mechanism explaining why cholangiocarcinoma often resists chemotherapy and identifies YB-1 as both a potential prognostic marker to predict treatment outcomes and a therapeutic target that could be blocked to restore sensitivity to cisplatin and other drugs in this highly lethal cancer.
⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Background and Aims: Intrahepatic cholangiocarcinoma (iCCA) is a tumor type with a high lethality due to late diagnosis and profound resistance to conventional chemotherapy. To date the molecular mechanisms underlying multidrug resistance remain poorly defined. Here, we integrate single-cell transcriptomics, clinicopathological analysis, and functional genomics to elucidate the molecular basis of cisplatin resistance in iCCA. Approach and Results: Single-cell RNA sequencing of iCCA and adjacent liver tissues revealed pronounced expression of Y-box-binding protein 1 (YB-1) in aneuploid malignant cholangiocarcinoma cells, with YB-1 expression progressively increasing during malignant evolution and strongly associated with chemoresistance. Clinically, elevated YB-1 expression, particularly its nuclear localization, robustly predicts poor overall survival and chemotherapy failure in patients with iCCA. Mechanistically, we demonstrate that cisplatin induces phosphorylation-dependent nuclear translocation of YB-1, enabling direct transcriptional activation of the drug efflux transporter ABCB1. Importantly, this process requires ABCB1 promoter demethylation, which is driven by cisplatin-induced, m6A-dependent destabilization of DNMT1 and DNMT3B mRNAs. This destabilization occurs through disruption of the YB-1-IGF2BP1/3-DNMT mRNA stabilizing complex and subsequent recruitment of DNMT transcripts to YTHDF2-mediated processing bodies for degradation. Conclusions: Our findings uncover a previously unrecognized YB-1-m6A-DNMT regulatory axis that drives chemotherapeutic resistance in iCCA, highlighting YB-1 as both a prognostic biomarker and a promising therapeutic target.