Epigenetic Regulation of Bmi1 by Ubiquitination and Proteasomal Degradation Inhibit Bcl-2 in Acute Myeloid Leukemia
Dr. Subhasree Roy Choudhury and group have recently shown that Polycomb protein Bmi1 is associated with advanced prognosis of acute myeloid leukemia (AML). Polyethylenimine (PEI)-stabilized Bmi1 siRNA-entrapped human serum albumin (HSA) nanocarriers (PEI@HSANCs) were used to protect siRNA from degradation and for epigenetic regulation-based AML therapy. Nanoform increased the transfection efficiency of Bmi1 siRNA through caveolae-mediated endocytosis and enhanced Bax translocation into the mitochondria, enhanced caspase 3-mediated apoptosisand inhibited Bcl2. The molecular analysis reveals the downregulation of polycomb proteins, Bmi1 and EzH2, along with inhibition of H3K27me3 and H2AK119ub1 through ubiquitin-mediated degradation of Bmi1, which is reversed by a proteasome inhibitor. Further mechanistic studies by Chromatin immunoprecipitation (ChIP) assay established a crucial role of transcription factor, C-Myb and Bmi1, as its direct targets for maintenance and progression of AML. Decreased leukemic stem cells marker (CD45+) and an increase in the myeloid differentiating marker expression (CD11b+) in the bone marrow,withdrawal of epigenetic repression through ubiquitin proteasomal pathway potentiating a novel antileukemic therapy were established in in vivo AML xenograft model.
More details: ACS Appl. Mater. Interfaces 2020, 12, 23, 25633–25644. https://doi.org/