CBX7 inhibits breast tumorigenicity through DKK-1-mediated suppression of the Wnt/β-catenin pathway
CBX7 inhibits breast tumorigenicity through DKK-1-mediated suppression of the Wnt/β-catenin pathway
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DOI：
10.1096/fj.14-253997
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发表时间：
2015-01-01
期刊：
影响因子：
4.8
通讯作者：
Kong, Gu
中科院分区：
文献类型：
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作者：
Kim, Hey-Yon;Park, Ji-Hye;Kong, Gu
多梳蛋白染色框同源物7(CBX7)参与多种生物学过程，包括干细胞调节和癌症发生，但其在乳腺癌中的作用尚不清楚。在这里，我们证明了CBX7负向调节乳腺肿瘤的发生。CD44(+)/CD24(-)/ESA(+)类乳腺干细胞CBX7表达减弱。此外，乳腺上皮细胞和癌细胞中的小发夹RNA介导的CBX7基因敲除增加了CD44(+)/CD24(-)/ESA(+)细胞的数量，并增强了体外自我更新和体内致瘤能力。同样，CBX7的过表达抑制了这些效应。我们还发现CBX7通过增强Wnt拮抗剂Dickkopf-1(DKK-1)的表达来抑制Wnt/b-catenin/T细胞因子途径。特别是，CBX7通过与p300乙酰转移酶协同增强DKK-1启动子的组蛋白乙酰化来增加DKK-1的转录。此外，药物抑制CBX7过表达细胞中的DKK-1可以恢复Wnt信号，从而挽救CD44(+)/CD24(-)/ESA(+)细胞群。综上所述，这些发现表明CBX7介导的DKK-1的表观遗传诱导对于抑制乳腺癌的致瘤性是至关重要的，这表明CBX7可能是一种潜在的乳腺癌抑制因子。
Polycomb protein chromobox homolog 7 (CBX7) is involved in several biologic processes including stem cell regulation and cancer development, but its roles in breast cancer remain unknown. Here, we demonstrate that CBX7 negatively regulates breast tumor initiation. CD44(+)/CD24(-)/ESA(+) breast stem-like cells showed diminished CBX7 expression. Furthermore, small hairpin RNA-mediated CBX7 knockdown in breast epithelial and cancer cells increased the CD44(+)/CD24(-)/ESA(+) cell population and reinforced in vitro self-renewal and in vivo tumor-initiating ability. Similarly, CBX7 overexpression repressed these effects. We also found that CBX7 inhibits the Wnt/b-catenin/T cell factor pathway by enhancing the expression of Dickkopf-1 (DKK-1), a Wnt antagonist. In particular, CBX7 increased DKK-1 transcription by cooperating with p300 acetyltransferase and subsequently enhancing the histone acetylation of the DKK-1 promoter. Furthermore, pharmacologic inhibition of DKK-1 in CBX7-overexpressing cells showed recovery of Wnt signaling and consequent rescue of the CD44(+)/CD24(-)/ESA(+) cell population. Taken together, these findings indicate that CBX7-mediated epigenetic induction of DKK-1 is crucial for the inhibition of breast tumorigenicity, suggesting that CBX7 could be a potential tumor suppressor in human breast cancer.