CCN6通过拮抗WNT/β-catenin信号来抑制EZH2驱动的EMT,从而抑制移行细胞乳腺癌。

IF 12.5 1区 医学 Q1 ONCOLOGY
Maria E Gonzalez, Bryce Brophy, Ahmad Eido, Adele E Leonetti, Sabra I Djomehri, Giuseppina Augimeri, Nicholas J Carruthers, Raymond G Cavalcante, Francesca Giordano, Sebastiano Andò, Alexey I Nesvizhskii, Eric R Fearon, Celina G Kleer
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引用次数: 0

摘要

移行细胞乳腺癌(mBrCAs)是三阴性乳腺癌(TNBC)的一种高度侵袭性亚型,组织学证据显示其存在上皮向间充质转化(EMT)和异常分化。抑癌基因CCN6(又称WISP3)失活是mBrCAs的一个特征,乳腺上皮细胞中Ccn6条件性失活的小鼠(Ccn6-KO)会患上具有EMT的纺锤形mBrCAs。阐明CCN6如何在mBrCA中充当肿瘤抑制因子的确切机制细节有助于确定更好的治疗策略。在这里,我们发现CCN6与mBrCA细胞上的Wnt受体FZD8和共受体LRP6相互作用,以拮抗Wnt诱导的β-catenin/TCF介导的转录激活。组蛋白甲基转移酶EZH2被鉴定为Ccn6-KO mBrCA细胞中β-catenin/TCF的转录靶标。抑制 Ccn6-KO mBrCA 细胞中的 Wnt/β-catenin/TCF 信号转导会导致 EZH2 表达减少、组蛋白 H3 赖氨酸 27 三甲基化降低以及特定靶基因的失调。药理抑制 EZH2 可减少 Ccn6-KO mBrCA 乳腺肿瘤在体内的生长和转移。与其他亚型相比,人纺锤体mBrCA中低CCN6与激活的β-catenin和高EZH2明显相关。总之,这些发现确定了CCN6是β-catenin/TCF-EZH2轴的关键负调控因子,并强调抑制β-catenin或EZH2是治疗纺锤体mBrCAs患者的一种潜在方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
CCN6 Suppresses Metaplastic Breast Carcinoma by Antagonizing Wnt/β-Catenin Signaling to Inhibit EZH2-Driven EMT.

Metaplastic breast carcinomas (mBrCA) are a highly aggressive subtype of triple-negative breast cancer with histologic evidence of epithelial-to-mesenchymal transition and aberrant differentiation. Inactivation of the tumor suppressor gene cellular communication network factor 6 (CCN6; also known as Wnt1-induced secreted protein 3) is a feature of mBrCAs, and mice with conditional inactivation of Ccn6 in mammary epithelium (Ccn6-KO) develop spindle mBrCAs with epithelial-to-mesenchymal transition. Elucidation of the precise mechanistic details of how CCN6 acts as a tumor suppressor in mBrCA could help identify improved treatment strategies. In this study, we showed that CCN6 interacts with the Wnt receptor FZD8 and coreceptor LRP6 on mBrCA cells to antagonize Wnt-induced activation of β-catenin/TCF-mediated transcription. The histone methyltransferase EZH2 was identified as a β-catenin/TCF transcriptional target in Ccn6-KO mBrCA cells. Inhibiting Wnt/β-catenin/TCF signaling in Ccn6-KO mBrCA cells led to reduced EZH2 expression, decreased histone H3 lysine 27 trimethylation, and deregulation of specific target genes. Pharmacologic inhibition of EZH2 reduced growth and metastasis of Ccn6-KO mBrCA mammary tumors in vivo. Low CCN6 is significantly associated with activated β-catenin and high EZH2 in human spindle mBrCAs compared with other subtypes. Collectively, these findings establish CCN6 as a key negative regulator of a β-catenin/TCF/EZH2 axis and highlight the inhibition of β-catenin or EZH2 as a potential therapeutic approach for patients with spindle mBrCAs.  Significance: CCN6 deficiency drives metaplastic breast carcinoma growth and metastasis by increasing Wnt/β-catenin activation to upregulate EZH2, identifying EZH2 inhibition as a mechanistically guided treatment strategy for this deadly form of breast cancer.

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来源期刊
Cancer research
Cancer research 医学-肿瘤学
CiteScore
16.10
自引率
0.90%
发文量
7677
审稿时长
2.5 months
期刊介绍: Cancer Research, published by the American Association for Cancer Research (AACR), is a journal that focuses on impactful original studies, reviews, and opinion pieces relevant to the broad cancer research community. Manuscripts that present conceptual or technological advances leading to insights into cancer biology are particularly sought after. The journal also places emphasis on convergence science, which involves bridging multiple distinct areas of cancer research. With primary subsections including Cancer Biology, Cancer Immunology, Cancer Metabolism and Molecular Mechanisms, Translational Cancer Biology, Cancer Landscapes, and Convergence Science, Cancer Research has a comprehensive scope. It is published twice a month and has one volume per year, with a print ISSN of 0008-5472 and an online ISSN of 1538-7445. Cancer Research is abstracted and/or indexed in various databases and platforms, including BIOSIS Previews (R) Database, MEDLINE, Current Contents/Life Sciences, Current Contents/Clinical Medicine, Science Citation Index, Scopus, and Web of Science.
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