通过抑制 LSD1 恢复 TFPI2 可抑制肿瘤进展并增强乳腺癌的抗肿瘤免疫力

IF 9.1 1区 医学 Q1 ONCOLOGY Cancer letters Pub Date : 2024-08-21 DOI:10.1016/j.canlet.2024.217182
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引用次数: 0

摘要

组蛋白赖氨酸特异性去甲基化酶1(LSD1)在三阴性乳腺癌(TNBC)中经常过表达,这与TNBC患者的临床预后较差有关。然而,LSD1 促进 TNBC 进展的潜在机制仍有待确定。最近,我们通过将乳腺条件性 LSD1 基因敲除小鼠与 Brca1 基因缺陷小鼠杂交,建立了一个基因工程小鼠模型,以探索 LSD1 在 TNBC 发病机制中的作用。Cre介导的Brca1缺失导致小鼠乳腺肿瘤形成的发生率升高,而LSD1的同时缺失阻碍了肿瘤的形成,这表明LSD1在促进Brca1缺失肿瘤的形成中起着关键作用。我们还证明了肿瘤抑制基因组织因子通路抑制因子2(TFPI2)的沉默与LSD1介导的TNBC进展在功能上相关。与正常乳腺组织相比,小鼠Brca1缺陷肿瘤表现出LSD1表达升高和TFPI2水平降低。对TCGA数据库的分析表明,在侵袭性ER阴性或基底样BC中,TFPI2的表达显著降低。通过抑制 LSD1 恢复 TFPI2 增加了 TFPI2 启动子处的 H3K4me2 富集,抑制了肿瘤的进展,增强了化疗药物的抗肿瘤效果。通过 LSD1 消融诱导 TFPI2 可下调基质金属蛋白酶(MMPs)的活性,进而增加肿瘤环境中吸引细胞毒性 T 淋巴细胞的趋化因子水平,导致 CD8+ T 细胞的肿瘤浸润增强。此外,在免疫原性差的 TNBC 中,诱导 TFPI2 能增强 LSD1 抑制剂和免疫检查点阻断剂的抗肿瘤作用。总之,我们的研究确定了 TFPI2 在 LSD1 介导的 TNBC 进展、治疗反应和免疫原性效应中以前未认识到的作用。
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Restoration of TFPI2 by LSD1 inhibition suppresses tumor progression and potentiates antitumor immunity in breast cancer

Histone lysine-specific demethylase 1 (LSD1) is frequently overexpressed in triple negative breast cancer (TNBC), which is associated with worse clinical outcome in TNBC patients. However, the underlying mechanisms by which LSD1 promotes TNBC progression remain to be identified. We recently established a genetically engineered murine model by crossing mammary gland conditional LSD1 knockout mice with Brca1-deficient mice to explore the role of LSD1 in TNBC pathogenesis. Cre-mediated Brca1 loss led to higher incidence of tumor formation in mouse mammary glands, which was hindered by concurrent depletion of LSD1, indicating a critical role of LSD1 in promoting Brca1-deficient tumors. We also demonstrated that the silencing of a tumor suppressor gene, Tissue Factor Pathway Inhibitor 2 (TFPI2), is functionally associated with LSD1-mediated TNBC progression. Mouse Brca1-deficient tumors exhibited elevated LSD1 expression and decreased TFPI2 level compared to normal mammary tissues. Analysis of TCGA database revealed that TFPI2 expression is significantly lower in aggressive ER-negative or basal-like BC. Restoration of TFPI2 through LSD1 inhibition increased H3K4me2 enrichment at the TFPI2 promoter, suppressed tumor progression, and enhanced antitumor efficacy of chemotherapeutic agent. Induction of TFPI2 by LSD1 ablation downregulates activity of matrix metalloproteinases (MMPs) that in turn increases the level of cytotoxic T lymphocyte attracting chemokines in tumor environment, leading to enhanced tumor infiltration of CD8+ T cells. Moreover, induction of TFPI2 potentiates antitumor effect of LSD1 inhibitor and immune checkpoint blockade in poorly immunogenic TNBC. Together, our study identifies previously unrecognized roles of TFPI2 in LSD1-mediated TNBC progression, therapeutic response, and immunogenic effects.

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来源期刊
Cancer letters
Cancer letters 医学-肿瘤学
CiteScore
17.70
自引率
2.10%
发文量
427
审稿时长
15 days
期刊介绍: Cancer Letters is a reputable international journal that serves as a platform for significant and original contributions in cancer research. The journal welcomes both full-length articles and Mini Reviews in the wide-ranging field of basic and translational oncology. Furthermore, it frequently presents Special Issues that shed light on current and topical areas in cancer research. Cancer Letters is highly interested in various fundamental aspects that can cater to a diverse readership. These areas include the molecular genetics and cell biology of cancer, radiation biology, molecular pathology, hormones and cancer, viral oncology, metastasis, and chemoprevention. The journal actively focuses on experimental therapeutics, particularly the advancement of targeted therapies for personalized cancer medicine, such as metronomic chemotherapy. By publishing groundbreaking research and promoting advancements in cancer treatments, Cancer Letters aims to actively contribute to the fight against cancer and the improvement of patient outcomes.
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