靶向肺癌中的 COMMD4-H2B 蛋白复合物。
Targeting the COMMD4-H2B protein complex in lung cancer.
机构信息
Queensland University of Technology (QUT), School of Biomedical Sciences, Centre for Genomics and Personalised Health at the Translational Research Institute, 37 Kent Street, Woolloongabba, QLD, 4102, Australia.
Frazer Institute, Faculty of Medicine, The University of Queensland at the Translational Research Institute, 37 Kent Street, Woolloongabba, QLD, 4102, Australia.
出版信息
Br J Cancer. 2023 Dec;129(12):2014-2024. doi: 10.1038/s41416-023-02476-8. Epub 2023 Nov 1.
BACKGROUND
Lung cancer is the biggest cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for 85-90% of all lung cancers. Identification of novel therapeutic targets are required as drug resistance impairs chemotherapy effectiveness. COMMD4 is a potential NSCLC therapeutic target. The aims of this study were to investigate the COMMD4-H2B binding pose and develop a short H2B peptide that disrupts the COMMD4-H2B interaction and mimics COMMD4 siRNA depletion.
METHODS
Molecular modelling, in vitro binding and site-directed mutagenesis were used to identify the COMMD4-H2B binding pose and develop a H2B peptide to inhibit the COMMD4-H2B interaction. Cell viability, DNA repair and mitotic catastrophe assays were performed to determine whether this peptide can specially kill NSCLC cells.
RESULTS
Based on the COMMD4-H2B binding pose, we have identified a H2B peptide that inhibits COMMD4-H2B by directly binding to COMMD4 on its H2B binding binding site, both in vitro and in vivo. Treatment of NSCLC cell lines with this peptide resulted in increased sensitivity to ionising radiation, increased DNA double-strand breaks and induction of mitotic catastrophe in NSCLC cell lines.
CONCLUSIONS
Our data shows that COMMD4-H2B represents a novel potential NSCLC therapeutic target.
背景
肺癌是全球癌症相关死亡的最大原因。非小细胞肺癌（NSCLC）占所有肺癌的 85-90%。由于耐药性会降低化疗效果，因此需要确定新的治疗靶点。COMMD4 是一种潜在的 NSCLC 治疗靶点。本研究旨在探究 COMMD4-H2B 结合构象，并开发一种短的 H2B 肽，以破坏 COMMD4-H2B 相互作用并模拟 COMMD4 siRNA 耗竭。
方法
采用分子建模、体外结合和定点突变等方法，确定 COMMD4-H2B 结合构象，并开发一种 H2B 肽以抑制 COMMD4-H2B 相互作用。通过细胞活力、DNA 修复和有丝分裂灾难检测等实验，来确定该肽是否可以特异性杀死 NSCLC 细胞。
结果
基于 COMMD4-H2B 的结合构象，我们确定了一种 H2B 肽，它可以通过直接结合 COMMD4 上的 H2B 结合结合位点，在体外和体内抑制 COMMD4-H2B。用该肽处理 NSCLC 细胞系可导致其对电离辐射更敏感，增加 DNA 双链断裂，并诱导 NSCLC 细胞系发生有丝分裂灾难。
结论
我们的数据表明，COMMD4-H2B 代表了一种新型潜在的 NSCLC 治疗靶点。
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