Epigenetic targeting of MECOM/KRAS axis by JIB-04 impairs tumorigenesis and cisplatin resistance in MECOM-amplified ovarian cancer.

IF 6.1 2区生物学 Q1 CELL BIOLOGY

Cell Death Discovery Pub Date : 2025-07-15 DOI:10.1038/s41420-025-02618-2

Ibha Singh, Amarnath Karna, Anita Prajapati, Ujjawal Solanki, Archana Mukherjee, Sheetal Uppal, Pawan Malhotra, Manoj Kumar, Pallavi Agarwal

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引用次数: 0

Abstract

Copy number gene amplification and associated overexpression of driver oncogenes are genetic events that contribute to cancer progression and drug resistance. MDS1 and EVI1 Complex locus (MECOM) gene is copy number amplified and overexpressed in aggressive epithelial ovarian cancers. The biological function and precise molecular mechanism of MECOM in the progression and drug resistance of ovarian cancer remain unclear. Here, we unravel MECOM as a regulator of KRAS and its downstream MAP Kinase signalling pathway, and also identify epigenetic inhibitor JIB-04 as a pharmacological agent targeting MECOM/KRAS axis. RNAi-mediated attenuation of MECOM in ovarian cancer cells harboring MECOM amplification reduced their proliferation, impaired colony formation, and impeded cellular migration. ChIP-qPCR analysis confirmed binding of MECOM to the KRAS promoter, suggesting direct regulation of the KRAS gene at the transcriptional level. Further, MECOM promoted cellular proliferation by regulating KRAS-mediated ERK/ZEB1 signalling cascade. The anti-tumorigenic effects due to MECOM loss were phenocopied by the treatment of ovarian cancer cells harboring MECOM amplification with JIB-04 epigenetic inhibitor targeting Jumonji domain histone demethylase enzymes. By ChIP-qPCR, we show that JIB-04 induced transcriptional changes of MECOM by altering H3K27me3 demethylation at its promoter region. We further report that ovarian cancer cells expressing high-MECOM levels exhibit cisplatin resistance, which could be effectively reversed upon pre-treatment with JIB-04. The therapeutic efficacy of JIB-04 was further demonstrated in mice bearing ovarian cancer cell xenografts, where JIB-04 slowed down the tumor growth in corroboration with diminishing MECOM expression. RNA-sequencing analysis identified potential cisplatin resistance gene, SUB1, being regulated by JIB-04-mediated modulation of MECOM expression. Altogether, these data suggest that epigenetic silencing of MECOM by JIB-04 mediated H3K27me3 modulation is an important mechanism in ovarian cancer and provide a new therapeutic target for the treatment of ovarian cancers harboring MECOM amplification.

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JIB-04对MECOM/KRAS轴的表观遗传靶向影响MECOM扩增卵巢癌的肿瘤发生和顺铂耐药性

拷贝数基因扩增和相关的驱动癌基因过表达是促进癌症进展和耐药的遗传事件。MDS1和EVI1复合物位点（MECOM）基因在侵袭性上皮性卵巢癌中拷贝数扩增和过表达。MECOM在卵巢癌进展和耐药中的生物学功能和确切的分子机制尚不清楚。在这里，我们揭示了MECOM作为KRAS及其下游MAP激酶信号通路的调节因子，并确定了表观遗传抑制剂JIB-04作为靶向MECOM/KRAS轴的药物。在携带MECOM扩增的卵巢癌细胞中，rnai介导的MECOM衰减降低了它们的增殖，破坏了集落形成，阻碍了细胞迁移。ChIP-qPCR分析证实MECOM与KRAS启动子结合，提示在转录水平上直接调控KRAS基因。此外，MECOM通过调节kras介导的ERK/ZEB1信号级联促进细胞增殖。通过靶向聚蒙基结构域组蛋白去甲基化酶的JIB-04表观遗传抑制剂对MECOM扩增的卵巢癌细胞进行治疗，MECOM缺失引起的抗肿瘤作用被表型化。通过ChIP-qPCR，我们发现JIB-04通过改变启动子区域的H3K27me3去甲基化诱导MECOM的转录变化。我们进一步报道，表达高mecom水平的卵巢癌细胞表现出顺铂耐药，这种耐药可以在JIB-04预处理后有效逆转。JIB-04的治疗效果在移植卵巢癌细胞的小鼠中得到进一步证实，JIB-04减缓了肿瘤的生长，这与减少MECOM的表达相一致。rna测序分析发现潜在的顺铂耐药基因SUB1受jib -04介导的MECOM表达调控。综上所述，这些数据表明，JIB-04介导的H3K27me3调控对MECOM的表观遗传沉默是卵巢癌的重要机制，为治疗含有MECOM扩增的卵巢癌提供了新的治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Death Discovery Biochemistry, Genetics and Molecular Biology-Cell Biology

CiteScore

8.30

自引率

1.40%

发文量

468

审稿时长

9 weeks

期刊介绍： Cell Death Discovery is a multidisciplinary, international, online-only, open access journal, dedicated to publishing research at the intersection of medicine with biochemistry, pharmacology, immunology, cell biology and cell death, provided it is scientifically sound. The unrestricted access to research findings in Cell Death Discovery will foster a dynamic and highly productive dialogue between basic scientists and clinicians, as well as researchers in industry with a focus on cancer, neurobiology and inflammation research. As an official journal of the Cell Death Differentiation Association (ADMC), Cell Death Discovery will build upon the success of Cell Death & Differentiation and Cell Death & Disease in publishing important peer-reviewed original research, timely reviews and editorial commentary. Cell Death Discovery is committed to increasing the reproducibility of research. To this end, in conjunction with its sister journals Cell Death & Differentiation and Cell Death & Disease, Cell Death Discovery provides a unique forum for scientists as well as clinicians and members of the pharmaceutical and biotechnical industry. It is committed to the rapid publication of high quality original papers that relate to these subjects, together with topical, usually solicited, reviews, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.