The E3 ubiquitin ligase MAEA promotes macrophage phagocytosis and inhibits gastrointestinal cancer progression by mediating PARP1 ubiquitination and degradation.

Abstract

Background: While a role for the E3 ubiquitin ligase MAEA (macrophage erythroblast attacher) has been reported in several cancer types, its importance and mechanistic functions in gastrointestinal cancer (GIC) have yet to be established. Methods: The functions of MAEA in GIC were explored through in vitro and in vivo experiments, including loss- and gain-of-function analyses. Mass spectrometry was used to identify proteins that interact with MAEA. The mechanisms through which MAEA influences tumor aggression were examined through immunoprecipitation analyses. Results: GIC patients exhibiting reduced expression of MAEA were found to exhibit worse disease-free and overall survival outcomes. MAEA was found to impair the proliferation and chemoresistance of GIC tumors in vitro and in subcutaneous xenograft model systems. The combination of MAEA and the PARP1 inhibitor veliparib resulted in enhanced oxaliplatin treatment efficacy in vivo. From a mechanistic perspective, MAEA was found to mediate the K48-linked ubiquitination and degradation of PARP1, in addition to suppressing the M2 polarization of macrophages and enhancing macrophage phagocytic activity. Conclusions: These data suggest that MAEA offers value as a prognostic biomarker and target for the treatment of GIC owing to its ability to degrade PARP1 and augment the phagocytic activity of macrophages.