Fbxw7 suppresses carcinogenesis and stemness in triple-negative breast cancer through CHD4 degradation and Wnt/β-catenin pathway inhibition.
Fbxw7 suppresses carcinogenesis and stemness in triple-negative breast cancer through CHD4 degradation and Wnt/β-catenin pathway inhibition.
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Fbxw7 通过 CHD4 降解和 Wnt/β-catenin 通路抑制来抑制三阴性乳腺癌的致癌和干性。
DOI：
10.1186/s12967-024-04897-2
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发表时间：
2024-01-24
影响因子：
7.4
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中科院分区：
文献类型：
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肿瘤干细胞（cancer stem cells，CSCs）是肿瘤组织中的一小部分细胞，可以驱动肿瘤发生并促进肿瘤进展。少数先前的研究间接提到了F-box和WD重复结构域7（FBXW 7）在三阴性乳腺癌（TNBC）中作为肿瘤抑制因子的作用。然而，很少有研究集中在FBXW 7在TNBC的癌症干化中的功能及其相关机制。我们采用免疫组化（IHC）方法检测了80例TNBC患者的FBXW 7。在MD-MBA-231和HCC 1937细胞模型中构建FBXW 7敲低和过表达。通过集落测定、流式细胞术、transwell测定、蛋白质印迹和球体形成测定来评估FBXW 7对恶性表型和干性的影响。免疫沉淀-质谱（IP-MS）和泛素化实验用于寻找和验证FBXW 7的潜在下游底物蛋白。构建动物实验以检查FBXW 7对体内TNBC细胞的致瘤潜力和癌症干性的影响。结果显示，FBXW 7在TNBC组织中呈低水平表达，与TNBC患者的预后呈正相关。在体外，FBXW 7显著抑制集落形成、细胞周期进程、细胞迁移、EMT过程、癌干细胞并促进凋亡。进一步的实验证实，chromodomain-helicase-DNA-binding protein 4（CHD 4）是FBXW 7的一个新的下游靶点，并通过蛋白酶体降解被FBXW 7下调。CHD 4可促进β-catenin的核转位，并逆转FBXW 7对β-catenin的抑制作用，最终激活Wnt/β-catenin通路。拯救实验证实FBXW 7-CHD 4-Wnt/β-连环蛋白轴参与调节TNBC细胞中CSC的维持。在动物实验中，FBXW 7降低CSC标志物表达并抑制体内TNBC细胞肿瘤发生。综上所述，这些结果突出了FBXW 7通过泛素化降解CHD 4蛋白，从而阻断Wnt/β-连环蛋白途径的激活以抑制TNBC细胞的干性。因此，靶向FBXW 7可能是针对TNBC的治疗性干预的有前景的策略。在线版本包含补充材料，可通过10.1186/s12967-024-04897-2获得。
Cancer stem cells (CSCs) are a small population of cells in tumor tissues that can drive tumor initiation and promote tumor progression. A small number of previous studies indirectly mentioned the role of F-box and WD repeat domain-containing 7 (FBXW7) as a tumor suppressor in Triple-negative breast cancer (TNBC). However, few studies have focused on the function of FBXW7 in cancer stemness in TNBC and the related mechanism. We detected FBXW7 by immunohistochemistry (IHC) in 80 TNBC patients. FBXW7 knockdown and overexpression in MD-MBA-231 and HCC1937 cell models were constructed. The effect of FBXW7 on malignant phenotype and stemness was assessed by colony assays, flow cytometry, transwell assays, western blot, and sphere formation assays. Immunoprecipitation-Mass Spectrometry (IP-MS) and ubiquitination experiments were used to find and verify potential downstream substrate proteins of FBXW7. Animal experiments were constructed to examine the effect of FBXW7 on tumorigenic potential and cancer stemness of TNBC cells in vivo. The results showed that FBXW7 was expressed at low levels in TNBC tissues and positively correlated with prognosis of TNBC patients. In vitro, FBXW7 significantly inhibited colony formation, cell cycle progression, cell migration, EMT process, cancer stemness and promotes apoptosis. Further experiments confirmed that chromodomain-helicase-DNA-binding protein 4 (CHD4) is a novel downstream target of FBXW7 and is downregulated by FBXW7 via proteasomal degradation. Moreover, CHD4 could promote the nuclear translocation of β-catenin and reverse the inhibitory effect of FBXW7 on β-catenin, and ultimately activate the Wnt/β-catenin pathway. Rescue experiments confirmed that the FBXW7-CHD4-Wnt/β-catenin axis was involved in regulating the maintenance of CSC in TNBC cells. In animal experiments, FBXW7 reduced CSC marker expression and suppressed TNBC cell tumorigenesis in vivo. Taken together, these results highlight that FBXW7 degrades CHD4 protein through ubiquitination, thereby blocking the activation of the Wnt/β-catenin pathway to inhibit the stemness of TNBC cells. Thus, targeting FBXW7 may be a promising strategy for therapeutic intervention against TNBC. The online version contains supplementary material available at 10.1186/s12967-024-04897-2.
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