Ortiz-Hernandez Greisha L, Sanchez-Hernandez Evelyn S, Ochoa Pedro T, Casiano Carlos A
Center for Health Disparities and Molecular Medicine, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA.
Department of Medicine, Division of Rheumatology, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA.
Cancers (Basel). 2024 Nov 26;16(23):3957. doi: 10.3390/cancers16233957.
The lens epithelium derived growth factor of 75 kD (LEDGF/p75) is a transcription co-activator and epigenetic reader that has emerged as a stress oncoprotein in multiple human cancers. Growing evidence indicates that it promotes tumor cell survival against certain therapeutic drugs. The amino (N)-terminal region of LEDGF/p75 contains a PWWP domain that reads methylated histone marks, critical for recognizing transcriptionally active chromatin sites. Its carboxyl (C)-terminus has an integrase binding domain (IBD) that serves as the binding site for the HIV-1 integrase and multiple oncogenic transcription factors. Acting as hubs for protein-protein interactions, both domains facilitate the tethering of oncogenic transcription factors and regulators to active chromatin to regulate mRNA splicing, promote DNA repair, and enhance the expression of stress and cancer-related genes that contribute to tumor cell aggressiveness and chemoresistance. This review summarizes our current knowledge of the emerging roles of LEDGF/p75 in cancer biology and therapy resistance and discusses its potential as a novel oncotherapeutic target in combinatorial treatments.
75千道尔顿的晶状体上皮衍生生长因子（LEDGF/p75）是一种转录共激活因子和表观遗传阅读器，已成为多种人类癌症中的应激癌蛋白。越来越多的证据表明，它能促进肿瘤细胞对某些治疗药物的存活。LEDGF/p75的氨基（N）末端区域包含一个PWWP结构域，该结构域读取甲基化组蛋白标记，这对于识别转录活跃的染色质位点至关重要。其羧基（C）末端有一个整合酶结合结构域（IBD），它是HIV-1整合酶和多种致癌转录因子的结合位点。作为蛋白质-蛋白质相互作用的枢纽，这两个结构域都有助于将致癌转录因子和调节因子拴系到活性染色质上，以调节mRNA剪接、促进DNA修复，并增强应激和癌症相关基因的表达，这些基因有助于肿瘤细胞的侵袭性和化疗耐药性。这篇综述总结了我们目前对LEDGF/p75在癌症生物学和治疗耐药性中新兴作用的认识，并讨论了其作为联合治疗中新型肿瘤治疗靶点的潜力。
