The Emerging Roles of the Stress Epigenetic Reader LEDGF/p75 in Cancer Biology and Therapy Resistance: Mechanisms and Targeting Opportunities.

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.