Molecular Mechanism of ZC3H13 -mediated Ferroptosis in Doxorubicin Resistance of Triple Negative Breast Cancer

Overview

Journal Cell Biol Toxicol

Publisher Springer

Specialties Cell Biology
Toxicology

Date 2025 Feb 25

PMID 40000487

Authors

Li Huang

Lei Han

Shuai Liang

Guohui Han

Affiliations

Soon will be listed here.

Abstract

Background: Triple negative breast cancer (TNBC) continues to be the most aggressive subtype of breast cancer that frequently develops resistance to chemotherapy. Doxorubicin (DOX) belongs to the anthracycline chemical class of the drug and is one of the widely used anticancer drugs. This study investigates the mechanism of m6A methyltransferase ZC3H13 in DOX resistance of TNBC.

Methods: ZC3H13, KCNQ1OT1, and TRABD expressions in TNBC tissues or cells were detected by RT-qPCR or Western blot. The effect of ZC3H13 on DOX resistance of TNBC cells was evaluated by CCK-8, clone formation, and EdU staining. RIP was performed to analyze the enrichment of YTHDF2 or m6A on KCNQ1OT1. RIP and RNA pull-down verified the binding between KCNQ1OT1 and MLL4. The enrichment of MLL or H3K9me1/2/3 on TRABD promoter was analyzed by ChIP. A nude mouse xenograft tumor model was established to verify the mechanism in vivo.

Results: ZC3H13 was poorly expressed in TNBC, and its expression further decreased in drug-resistant cells. Overexpression of ZC3H13 decreased the IC50 of drug-resistant TNBC cells to DOX, repressed proliferation, and induced ferroptosis. Mechanistically, ZC3H13-mediated m6A modification reduced the transcriptional stability of KCNQ1OT1 and inhibited its expression in a YTHDF2-dependent manner. KCNQ1OT1 enhanced the enrichment of H3K4me1/2/3 on TRABD promoter by recruiting MLL4, thus increasing TRABD expression. ZC3H13 induced ferroptosis by inhibiting KCNQ1OT1/TRABD, thereby restraining the growth of DOX-treated tumors in vivo.

Conclusion: ZC3H13-mediated m6A modification reduces DOX resistance in TNBC by promoting ferroptosis via KCNQ1OT1/TRABD axis.

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