ZC3H13介导的铁下垂在三阴性乳腺癌阿霉素耐药中的分子机制。

IF 5.9 2区 医学 Q2 CELL BIOLOGY
Li Huang, Lei Han, Shuai Liang, Guohui Han
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引用次数: 0

摘要

背景:三阴性乳腺癌(TNBC)仍然是最具侵袭性的乳腺癌亚型,经常对化疗产生耐药性。多柔比星(DOX)属于蒽环类化学药物,是目前应用广泛的抗癌药物之一。本研究探讨m6A甲基转移酶ZC3H13在TNBC耐药中的作用机制。方法:采用RT-qPCR或Western blot检测TNBC组织或细胞中ZC3H13、kcnq10t1、TRABD的表达。通过CCK-8、克隆形成和EdU染色评价ZC3H13对TNBC细胞DOX耐药的影响。利用RIP分析YTHDF2或m6A在kcnq10t1上的富集情况。RIP和RNA pull-down验证了kcnq10t1与MLL4的结合。用ChIP分析了TRABD启动子上MLL或H3K9me1/2/3的富集情况。建立裸鼠异种移植瘤模型,验证其体内机制。结果:ZC3H13在TNBC中表达较低,在耐药细胞中表达进一步降低。ZC3H13过表达降低耐药TNBC细胞对DOX的IC50,抑制增殖,诱导铁凋亡。在机制上,zc3h13介导的m6A修饰降低了kcnq10t1的转录稳定性,并以依赖ythdf2的方式抑制其表达。kcnq10t1通过募集MLL4增强TRABD启动子上H3K4me1/2/3的富集,从而增加TRABD的表达。ZC3H13通过抑制kcnq10t1 /TRABD诱导铁下垂,从而抑制dox治疗肿瘤的体内生长。结论:zc3h13介导的m6A修饰通过kcnq10t1 /TRABD轴促进铁凋亡,从而降低TNBC对DOX的耐药性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Molecular mechanism of ZC3H13 -mediated ferroptosis in doxorubicin resistance of triple negative breast cancer.

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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来源期刊
Cell Biology and Toxicology
Cell Biology and Toxicology 生物-毒理学
CiteScore
9.90
自引率
4.90%
发文量
101
审稿时长
>12 weeks
期刊介绍: Cell Biology and Toxicology (CBT) is an international journal focused on clinical and translational research with an emphasis on molecular and cell biology, genetic and epigenetic heterogeneity, drug discovery and development, and molecular pharmacology and toxicology. CBT has a disease-specific scope prioritizing publications on gene and protein-based regulation, intracellular signaling pathway dysfunction, cell type-specific function, and systems in biomedicine in drug discovery and development. CBT publishes original articles with outstanding, innovative and significant findings, important reviews on recent research advances and issues of high current interest, opinion articles of leading edge science, and rapid communication or reports, on molecular mechanisms and therapies in diseases.
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