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%。由于耐药性会损害化疗效果，因此需要确定新的治疗靶点。 COMMD4 是一个潜在的 NSCLC 治疗靶点。本研究的目的是研究 COMMD4-H2B 结合姿势并开发一种短 H2B 肽，该肽可破坏 COMMD4-H2B 相互作用并模拟 COMMD4 siRNA 耗竭。使用分子建模、体外结合和定点诱变来鉴定 COMMD4 -H2B 结合形成并形成 H2B 肽以抑制 COMMD4-H2B 相互作用。我们进行了细胞活力、DNA 修复和有丝分裂灾难测定，以确定该肽是否可以特异性杀死 NSCLC 细胞。根据 COMMD4-H2B 结合姿势，我们鉴定了一种 H2B 肽，该肽通过直接与其 H2B 上的 COMMD4 结合来抑制 COMMD4-H2B体外和体内的结合位点。用这种肽治疗 NSCLC 细胞系会导致 NSCLC 细胞系对电离辐射的敏感性增加、DNA 双链断裂增加并诱导有丝分裂灾难。我们的数据表明 COMMD4-H2B 代表了一种新的潜在 NSCLC 治疗靶点。© 2023。作者。

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.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.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.Our data shows that COMMD4-H2B represents a novel potential NSCLC therapeutic target.© 2023. The Author(s).