HEMATOLOGY / RESEARCH PAPER
UBC9 silencing-mediated PPARα desumoylation induces inhibition of cell proliferation by ferroptosis in acute myeloid leukemia
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Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, China
Submission date: 2024-02-04
Final revision date: 2024-06-26
Acceptance date: 2025-04-22
Online publication date: 2025-06-08
Corresponding author
Jianping Lan
Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, China
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ABSTRACT
Introduction:
Inhibited acute myeloid leukemia (AML) proliferation is accompanied by downregulated peroxisome proliferator-activated receptor alpha (PPARα), which however can be stabilized via sumoylation. This study investigated how PPARα sumoylation impacts on AML cell growth.
Material and methods:
Human AML HL-60 and tohoku hospital pediatrics-1 (THP-1) cells were treated with the PPARα inhibitor, GW6471 (10 µM), for 24 and 48 h. THP-1 cells were exposed to the PPARα agonist, pirinixic acid (10 µM), after the expression of the small ubiquitin-like modifier proteins (SUMO)-conjugating enzyme UBC9 was manipulated. The interaction between PPARα and SUMO1 was detected by immunoprecipitation assay. HL-60 and THP-1 cell viability, apoptosis and ferroptosis were measured via cell counting kit-8 assay, flow cytometry, BODIPY-C11 staining and/or colorimetric assay. UBC9, glutathione peroxidase 4 (GPX4), recombinant solute carrier family 7, member 11(SLC7A11) and PPARα expressions were analyzed by qRT-PCR or Western blot.
Results:
GW6471 treatment for 24 and 48 h suppressed viability, promoted apoptosis and lipid peroxidation, increased the level of Fe2+, and decreased the expressions of GPX4, SLC7A11 and PPARα in HL-60/THP-1 cells. PPARα antibody induced enrichment of PPARα and SUMO1 in THP-1 cells, which was attenuated after UBC9 silencing. UBC9 silencing resulted in viability decrease, apoptosis and lipid peroxidation promotion, Fe2+ upregulation, and GPX4, SLC7A11 and PPARα downregulation in THP-1 cells, which were all counteracted by pirinixic acid.
Conclusions:
UBC9 silencing-induced PPARα desumoylation induces suppression of AML cell growth by ferroptosis.