Deciphering MARCH5's impact on multiple myeloma: insights into autophagy regulation and AKT-FOXO3 signaling

Multiple myeloma (MM) stands as a formidable blood malignancy, necessitating innovative therapeutic approaches. Excessive immunoglobulin production within myeloma cells leads to a buildup of toxic proteins, and autophagy plays a crucial role in their survival by degrading toxic aggregates and generating energy. Membrane-associated RING finger protein 5 (MARCH5) is an E3-ligase positioned at the outer mitochondrial membrane and has been shown to regulate autophagy by competing for MicroRNA 30a (MIR30A). Given the fundamental significance of autophagy in promoting the survival of myeloma cells, coupled with the regulatory role of MARCH5 in autophagic activity, we hypothesized that MARCH5 plays an essential function in MM and holds a pivotal position in the pathogenesis and progression of MM. We identified MARCH5's unique dependencies in MM cells by analyzing the Cancer Dependency Map, thereby establishing its significance in MM biology. Examining various data sets, including CoMMpass (Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile Study) and HOVON (Haemato-Oncology Foundation for Adults in the Netherlands), demonstrated a correlation between MARCH5 expression and patient outcomes. Knockdown of MARCH5 revealed a substantial reduction in MM cell viability, which was associated with a decrease in autophagic activity. Mechanistically, we unraveled a novel MARCH5/AKT/FOXO3 axis, wherein MARCH5 regulates autophagy through the Protein Kinase B (AKT)-mediated degradation of Forkhead Box O3 (FOXO3). Compromised MM cell viability observed with MARCH5 knockdown was recapitulated in FOXO3 knockdown experiments, validating the pivotal role of FOXO3 in mediating MARCH5's effects. In conclusion, this research highlights the crucial role of MARCH5 in MM, and the identified MARCH5/AKT/FOXO3 axis enhances our understanding of MM biology and provides a foundation for developing targeted therapies.