Center for Health Disparities and Molecular Medicine, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA.
Department of Physiology, Faculty of Medicine, University of Jeddah, Jeddah 21577, Saudi Arabia.
Cells. 2021 Oct 12;10(10):2723. doi: 10.3390/cells10102723.
Patients with prostate cancer (PCa) receiving docetaxel chemotherapy invariably develop chemoresistance. The transcription co-activator lens epithelium-derived growth factor p75 (LEDGF/p75), also known as DFS70 and PSIP1, is upregulated in several human cancers, including PCa and promotes resistance to docetaxel and other drugs. The C-terminal region of LEDGF/p75 contains an integrase binding domain (IBD) that tethers nuclear proteins, including the HIV-1 integrase and transcription factors, to active chromatin to promote viral integration and transcription of cellular survival genes. Here, we investigated the contribution of the LEDGF/p75 IBD interactome to PCa chemoresistance. Quantitative immunoblotting revealed that LEDGF/p75 and its IBD-interacting partners are endogenously upregulated in docetaxel-resistant PCa cell lines compared to docetaxel-sensitive parental cells. Using specific human autoantibodies, we co-immunoprecipitated LEDGF/p75 with its endogenous IBD-interacting partners JPO2, menin, MLL, IWS1, ASK1, and PogZ, as well as transcription factors c-MYC and HRP2, in docetaxel-resistant cells, and confirmed their nuclear co-localization by confocal microscopy. Depletion of LEDGF/p75 and selected interacting partners robustly decreased the survival, clonogenicity, and tumorsphere formation capacity of docetaxel-resistant cells. These results implicate the LEDGF/p75 IBD interactome in PCa chemoresistance and could lead to novel therapeutic strategies targeting this protein complex for the treatment of docetaxel-resistant tumors.
接受多西紫杉醇化疗的前列腺癌 (PCa) 患者不可避免地会产生化疗耐药性。转录共激活因子晶状体上皮衍生生长因子 p75 (LEDGF/p75)，也称为 DFS70 和 PSIP1，在包括 PCa 在内的几种人类癌症中上调，并促进对多西紫杉醇和其他药物的耐药性。LEDGF/p75 的 C 端区域包含一个整合酶结合域 (IBD)，可将核蛋白（包括 HIV-1 整合酶和转录因子）固定在活性染色质上，以促进病毒整合和细胞存活基因的转录。在这里，我们研究了 LEDGF/p75 IBD 相互作用组对 PCa 化疗耐药性的贡献。定量免疫印迹显示，与多西紫杉醇敏感的亲本细胞相比，多西紫杉醇耐药的 PCa 细胞系中内源性地上调了 LEDGF/p75 及其 IBD 相互作用伙伴。使用特异性人自身抗体，我们共免疫沉淀了 LEDGF/p75 与其内源性 IBD 相互作用伙伴 JPO2、menin、MLL、IWS1、ASK1 和 PogZ 以及转录因子 c-MYC 和 HRP2 在多西紫杉醇耐药细胞中，并通过共聚焦显微镜证实了它们的核共定位。LEDGF/p75 和选定的相互作用伙伴的耗竭显着降低了多西紫杉醇耐药细胞的存活、集落形成能力和肿瘤球体形成能力。这些结果表明 LEDGF/p75 IBD 相互作用组参与了 PCa 的化疗耐药性，并可能导致针对该蛋白复合物的新型治疗策略，用于治疗多西紫杉醇耐药肿瘤。
