Department of Laboratory Medicine, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, 511518, Qingyuan, China.
Department of Clinical Laboratory, The Fifth Affiliated Hospital of Sun Yat-sen University, 519000, Zhuhai, Guangdong, China.
Cell Death Dis. 2022 Sep 10;13(9):781. doi: 10.1038/s41419-022-05223-8.
Zinc finger proteins (ZNFs) have been demonstrated to participate extensively in breast cancer progression by functioning as transcription factors, but there are still a variety of ZNFs whose biological mechanisms remain unknown. Here, we show that zinc finger protein 276 (ZNF276) is highly expressed in breast cancer tissues and cell lines. Higher level of ZNF276 correlated with poor prognosis. Gain-of and loss-of function suggested that ZNF276 is essential for the proliferation, migration and invasion of breast cancer cells in vitro and metastasis in vivo. RNA-sequencing and CUT&Tag assay revealed that ZNF276 controlled a variety of growth and metastasis-related genes expression. ZNF276 transcriptionally promoted the expression of CYP1B1 by directly binds to the promoter region of the CYP1B1 through its CH domain. ZNF276 facilitated the translocation of β-catenin from cytoplasm to nucleus through CYP1B1, leading to the upregulation of cyclin D1 and c-Myc, and the activation of the Wnt/β-catenin pathway. Knockdown of CYP1B1 significantly blocked the ZNF276-mediated effects on cell proliferation, migration and invasion. Lastly, ZNF276 interacted with MAGEB2 which enhanced the binding of ZNF276 at the CYP1B1 promoter, promoted CYP1B1 expression and Wnt signaling activation. Collectively, these findings highlight the oncogenic role of ZNF276 on breast cancer cell proliferation and metastasis. Targeting ZNF276/MAGEB2 axis may serve as a potential therapeutic strategy for breast cancer patients.
锌指蛋白（ZNFs）已被证明通过作为转录因子广泛参与乳腺癌的进展，但仍有多种 ZNFs 的生物学机制尚不清楚。在这里，我们表明锌指蛋白 276（ZNF276）在乳腺癌组织和细胞系中高度表达。ZNF276 水平较高与预后不良相关。功能获得和功能丧失实验表明，ZNF276 对于乳腺癌细胞在体外的增殖、迁移和侵袭以及体内转移是必需的。RNA-seq 和 CUT&Tag 实验揭示了 ZNF276 通过其 CH 结构域直接结合 CYP1B1 启动子区域，控制多种生长和转移相关基因的表达。ZNF276 通过 CYP1B1 促进 β-连环蛋白从细胞质向细胞核易位，导致 cyclin D1 和 c-Myc 的上调，以及 Wnt/β-连环蛋白信号通路的激活。CYP1B1 的敲低显著阻断了 ZNF276 对细胞增殖、迁移和侵袭的介导作用。最后，ZNF276 与 MAGEB2 相互作用，增强了 ZNF276 在 CYP1B1 启动子上的结合，促进了 CYP1B1 的表达和 Wnt 信号的激活。总之，这些发现强调了 ZNF276 在乳腺癌细胞增殖和转移中的致癌作用。靶向 ZNF276/MAGEB2 轴可能成为乳腺癌患者的一种潜在治疗策略。
