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HEMATOLOGY / EXPERIMENTAL RESEARCH
UBC9 silencing-mediated PPARa deSUMOylation induces inhibition of cell proliferation by ferroptosis in acute myeloid leukemia
1
Cancer center, Department of Hematology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 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
Cancer Center Department of Hematology Zhejiang Provincial People’s Hospital Affiliated People’s Hospital Hangzhou Medical College 158 Shangtang Road Hangzhou, Zhejiang Province 310014, China Phone: 86-571-87666666
Cancer Center Department of Hematology Zhejiang Provincial People’s Hospital Affiliated People’s Hospital Hangzhou Medical College 158 Shangtang Road Hangzhou, Zhejiang Province 310014, China Phone: 86-571-87666666
KEYWORDS
TOPICS
ABSTRACT
Introduction:
Inhibited acute myeloid leukemia (AML) proliferation is accompanied by downregulated peroxisome proliferator-activated receptor a (PPARa), which however can be stabilized via SUMOylation. This study investigated how PPARa SUMOylation impacts AML cell growth.
Material and methods:
Human AML HL-60 and Tohoku Hospital Pediatrics-1 (THP-1) cells were treated with the PPARa inhibitor GW6471 (10 µM) for 24 and 48 h. THP-1 cells were exposed to the PPARa agonist pirinixic acid (10 µM) following manipulation of the expression of the small ubiquitin-like modifier protein (SUMO)-conjugating enzyme UBC9. The interaction between PPARa 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 PPARa expression levels 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 expression of GPX4, SLC7A11 and PPARa in HL-60/THP-1 cells. PPARa antibody induced enrichment of PPARa 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 PPARa downregulation in THP-1 cells, which were all counteracted by pirinixic acid.
Conclusions:
UBC9 silencing-induced PPARa deSUMOylation induces suppression of AML cell growth by ferroptosis.
Inhibited acute myeloid leukemia (AML) proliferation is accompanied by downregulated peroxisome proliferator-activated receptor a (PPARa), which however can be stabilized via SUMOylation. This study investigated how PPARa SUMOylation impacts AML cell growth.
Material and methods:
Human AML HL-60 and Tohoku Hospital Pediatrics-1 (THP-1) cells were treated with the PPARa inhibitor GW6471 (10 µM) for 24 and 48 h. THP-1 cells were exposed to the PPARa agonist pirinixic acid (10 µM) following manipulation of the expression of the small ubiquitin-like modifier protein (SUMO)-conjugating enzyme UBC9. The interaction between PPARa 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 PPARa expression levels 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 expression of GPX4, SLC7A11 and PPARa in HL-60/THP-1 cells. PPARa antibody induced enrichment of PPARa 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 PPARa downregulation in THP-1 cells, which were all counteracted by pirinixic acid.
Conclusions:
UBC9 silencing-induced PPARa deSUMOylation induces suppression of AML cell growth by ferroptosis.
REFERENCES (44)
1.
Pelcovits A, Niroula R. Acute myeloid leukemia: a review. R I Med J (2013) 2020; 103: 38-40.
2.
Sasaki K, Ravandi F, Kadia T M, et al. De novo acute myeloid leukemia: a population-based study of outcome in the United States based on the Surveillance, Epidemiology, and End Results (SEER) database, 1980 to 2017. Cancer 2021; 127: 2049-61.
3.
Döhner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N Engl J Med 2015; 373: 1136-52.
4.
Bakhtiyari M, Liaghat M, Aziziyan F, et al. The role of bone marrow microenvironment (BMM) cells in acute myeloid leukemia (AML) progression: immune checkpoints, metabolic checkpoints, and signaling pathways. Cell Commun Signal 2023; 21: 252.
5.
Thol F, Ganser A. Treatment of relapsed acute myeloid leukemia. Curr Treat Options Oncol 2020; 21: 66.
6.
Xu T, Ding W, Ji X, et al. Molecular mechanisms of ferroptosis and its role in cancer therapy. J Cell Mol Med 2019; 23: 4900-12.
7.
Sun Y, Chen P, Zhai B, et al. The emerging role of ferroptosis in inflammation. Biomed Pharmacother 2020; 127: 110108.
8.
Gaschler MM, Andia AA, Liu H, et al. FINO2 initiates ferroptosis through GPX4 inactivation and iron oxidation. Nat Chem Biol 2018; 14: 507-15.
9.
Koppula P, Zhang Y, Zhuang L, et al. Amino acid transporter SLC7A11/xCT at the crossroads of regulating redox homeostasis and nutrient dependency of cancer. Cancer Commun 2018; 38: 12.
10.
Birsen R, Larrue C, Decroocq J, et al. APR-246 induces early cell death by ferroptosis in acute myeloid leukemia. Haematologica 2022; 107: 403-16.
11.
Yu Y, Xie Y, Cao L, et al. The ferroptosis inducer erastin enhances sensitivity of acute myeloid leukemia cells to chemotherapeutic agents. Mol Cell Oncol 2015; 2: e1054549.
12.
Jiang X, Stockwell BR, Conrad M. Ferroptosis: mechanisms, biology and role in disease. Nat Rev Mol Cell Biol 2021; 22: 266-82.
14.
Rezzola S, Sigmund EC, Halin C, et al. The lymphatic vasculature: an active and dynamic player in cancer progression. Med Res Rev 2022; 42: 576-614.
15.
Pawlak M, Lefebvre P, Staels B. Molecular mechanism of PPARa action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease. J Hepatol 2015; 62: 720-33.
16.
Lee JY, Nam M, Son HY, et al. Polyunsaturated fatty acid biosynthesis pathway determines ferroptosis sensitivity in gastric cancer. Proc Natl Acad Sci USA 2020; 117: 32433-42.
17.
Venkatesh D, O’Brien NA, Zandkarimi F, et al. MDM2 and MDMX promote ferroptosis by PPARa-mediated lipid remodeling. Genes Dev 2020; 34: 526-43.
18.
Han ZJ, Feng YH, Gu BH, et al. The post-translational modification, SUMOylation, and cancer (Review). Int J Oncol 2018; 52: 1081-94.
20.
Liu Y, Dou X, Zhou WY, et al. Hepatic small ubiquitin-related modifier (SUMO)-specific protease 2 controls systemic metabolism through SUMOylation-dependent regulation of liver-adipose tissue crosstalk. Hepatology 2021; 74: 1864-83.
21.
Zhang J, Huang FF, Wu DS, et al. SUMOylation of insulin-like growth factor 1 receptor, promotes proliferation in acute myeloid leukemia. Cancer Lett 2015; 357: 297-306.
22.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 2001; 25: 402-8.
23.
Vago L, Gojo I. Immune escape and immunotherapy of acute myeloid leukemia. J Clin Invest 2020; 130: 1552-64.
24.
Carter JL, Hege K, Yang J, et al. Targeting multiple signaling pathways: the new approach to acute myeloid leukemia therapy. Signal Transduct Target Ther 2020; 5: 288.
25.
Kayser S, Levis MJ. Advances in targeted therapy for acute myeloid leukaemia. Br J Haematol 2018; 180: 484-500.
26.
Zhang Y, Xing Z, Liu T, et al. Targeted therapy and drug resistance in thyroid cancer. Eur J Med Chem 2022; 238: 114500.
27.
Michalik L, Desvergne B, Wahli W. Peroxisome-proliferator-activated receptors and cancers: complex stories. Nat Rev Cancer 2004; 4: 61-70.
28.
Kersten S. Integrated physiology and systems biology of PPARa. Mol Metab 2014; 3: 354-71.
29.
Leng J, Li H, Niu Y, et al. Low-dose mono(2-ethylhexyl) phthalate promotes ovarian cancer development through PPARa-dependent PI3K/Akt/NF-kB pathway. Sci Total Environ 2021; 790: 147990.
30.
Luo Y, Xie C, Brocker CN, et al. Intestinal PPARa protects against colon carcinogenesis via regulation of methyltransferases DNMT1 and PRMT6. Gastroenterology 2019; 157: 744-59.e4.
31.
Luo X, Zhong L, Yu L, et al. TRIB3 destabilizes tumor suppressor PPARa expression through ubiquitin-mediated proteasome degradation in acute myeloid leukemia. Life Sci 2020; 257: 118021.
32.
Wang YX, Lee CH, Tiep S, et al. Peroxisome-proliferator-activated receptor delta activates fat metabolism to prevent obesity. Cell 2003; 113: 159-70.
33.
Kok T, Wolters H, Bloks VW, et al. Induction of hepatic ABC transporter expression is part of the PPARalpha-mediated fasting response in the mouse. Gastroenterology 2003; 124: 160-71.
34.
Kersten S. Peroxisome proliferator activated receptors and lipoprotein metabolism. PPAR Res 2008; 2008: 132960.
35.
Doll S, Proneth B, Tyurina YY, et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol 2017; 13: 91-8.
36.
Sun N, Shen C, Zhang L, et al. Hepatic Krüppel-like factor 16 (KLF16) targets PPARa to improve steatohepatitis and insulin resistance. Gut 2021; 70: 2183-95.
37.
Xie Y, Hou W, Song X, et al. Ferroptosis: process and function. Cell Death Differ 2016; 23: 369-79.
38.
Maiorino M, Conrad M, Ursini F. GPx4, lipid peroxidation, and cell death: discoveries, rediscoveries, and open issues. Antioxid Redox Signal 2018; 29: 61-74.
39.
Wu X, Li Y, Zhang S, et al. Ferroptosis as a novel therapeutic target for cardiovascular disease. Theranostics 2021; 11: 3052-9.
40.
Liu DS, Duong CP, Haupt S, et al. Inhibiting the system x(C)(-)/glutathione axis selectively targets cancers with mutant-p53 accumulation. Nat Commun 2017; 8: 14844.
41.
Linkermann A, Stockwell BR, Krautwald S, et al. Regulated cell death and inflammation: an auto-amplification loop causes organ failure. Nat Rev Immunol 2014; 14: 759-67.
42.
Li Q, Su R, Bao X, et al. Glycyrrhetinic acid nanoparticles combined with ferrotherapy for improved cancer immunotherapy. Acta Biomater 2022; 144: 109-20.
43.
Du Y, Bao J, Zhang MJ, et al. Targeting ferroptosis contributes to ATPR-induced AML differentiation via ROS-autophagy-lysosomal pathway. Gene 2020; 755: 144889.
44.
Hendriks IA, Vertegaal AC. A comprehensive compilation of SUMO proteomics. Nat Rev Mol Cell Biol 2016; 17: 581-95.
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| eISSN: | 1896-9151 |
| ISSN: | 1734-1922 |
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