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Prohibitin participates in the HIRA complex to promote cell metastasis in breast cancer cell lines.
FEBS Open Bio ( IF 2.8 ) Pub Date : 2020-08-31 , DOI: 10.1002/2211-5463.12966
Xiaoqing Huang 1 , Jinji Liu 1 , Qinghui Ma 1
Affiliation  

Prohibitin (PHB) is a highly conserved, ubiquitously expressed, multifunctional protein with a well‐characterized function as a chaperone‐stabilizing mitochondrial proteins. Recently it was reported that nuclear PHB participates in HIRA chaperone complexes and regulates downstream gene expression via cell cycle independent deposition of H3.3 into DNA. However, the role of PHB in cancer progression remains controversial with conflicting reports in the literature, perhaps due to its cell type‐dependent subcellular localization. Here, we report that the increased expression of nuclear PHB is positively correlated with metastasis of breast cancer cell lines. We showed PHB participates in the HIRA complex by interacting with HIRA through the linker region of the PHB domain and stabilizes all components of the HIRA complex in breast cancer. Overexpression of nuclear PHB resulted in a higher enrichment of histone H3.3 deposited by the HIRA complex at the promoters of mesenchymal markers. This coincided with an increased gene expression level of these markers, and induced EMT in breast cancer. Overall, these molecular and structural mechanisms suggest that nuclear PHB could hold promise as a potential target for cancer therapy.

中文翻译:

Prohibitin 参与 HIRA 复合物以促进乳腺癌细胞系中的细胞转移。

Prohibitin (PHB) 是一种高度保守、广泛表达的多功能蛋白,具有作为稳定线粒体蛋白的分子伴侣的功能。最近有报道称,核 PHB 参与 HIRA 伴侣复合物,并通过不依赖细胞周期的 H3.3 将 H3.3 沉积到 DNA 中来调节下游基因表达。然而,PHB 在癌症进展中的作用仍存在争议,文献报道相互矛盾,这可能是由于其细胞类型依赖的亚细胞定位。在这里,我们报告核 PHB 的表达增加与乳腺癌细胞系的转移呈正相关。我们展示了 PHB 通过 PHB 结构域的接头区域与 HIRA 相互作用来参与 HIRA 复合物,并稳定乳腺癌中 HIRA 复合物的所有成分。核 PHB 的过表达导致由 HIRA 复合物沉积在间充质标志物启动子处的组蛋白 H3.3 的更高富集。这与这些标志物的基因表达水平增加相吻合,并在乳腺癌中诱导 EMT。总体而言,这些分子和结构机制表明,核 PHB 有望成为癌症治疗的潜在靶点。
更新日期:2020-10-02
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