Skip to main content
SpringerLink
Log in

ACSL5, a prognostic factor in acute myeloid leukemia, modulates the activity of Wnt/β-catenin signaling by palmitoylation modification

  • Research Article
  • Published:
Frontiers of Medicine Aims and scope Submit manuscript

Abstract

Acyl-CoA synthetase long chain family member 5 (ACSL5), is a member of the acyl-CoA synthetases (ACSs) family that activates long chain fatty acids by catalyzing the synthesis of fatty acyl-CoAs. The dysregulation of ACSL5 has been reported in some cancers, such as glioma and colon cancers. However, little is known about the role of ACSL5 in acute myeloid leukemia (AML). We found that the expression of ACSL5 was higher in bone marrow cells from AML patients compared with that from healthy donors. ACSL5 level could serve as an independent prognostic predictor of the overall survival of AML patients. In AML cells, the ACSL5 knockdown inhibited cell growth both in vitro and in vivo. Mechanistically, the knockdown of ACSL5 suppressed the activation of the Wnt/β-catenin pathway by suppressing the palmitoylation modification of Wnt3a. Additionally, triacsin c, a pan-ACS family inhibitor, inhibited cell growth and robustly induced cell apoptosis when combined with ABT-199, the FDA approved BCL-2 inhibitor for AML therapy. Our results indicate that ACSL5 is a potential prognosis marker for AML and a promising pharmacological target for the treatment of molecularly stratified AML.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Yan P, Frankhouser D, Murphy M, Tam HH, Rodriguez B, Curfman J, Trimarchi M, Geyer S, Wu YZ, Whitman SP, Metzeler K, Walker A, Klisovic R, Jacob S, Grever MR, Byrd JC, Bloomfield CD, Garzon R, Blum W, Caligiuri MA, Bundschuh R, Marcucci G. Genome-wide methylation profiling in decitabine-treated patients with acute myeloid leukemia. Blood 2012; 120(12): 2466–2474

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Roboz GJ. Current treatment of acute myeloid leukemia. Curr Opin Oncol 2012; 24(6): 711–719

    Article  CAS  PubMed  Google Scholar 

  3. Watkins PA, Maiguel D, Jia Z, Pevsner J. Evidence for 26 distinct acyl-coenzyme A synthetase genes in the human genome. J Lipid Res 2007; 48(12): 2736–2750

    Article  CAS  PubMed  Google Scholar 

  4. Ellis JM, Frahm JL, Li LO, Coleman RA. Acyl-coenzyme A synthetases in metabolic control. Curr Opin Lipidol 2010; 21(3): 212–217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Klett EL, Chen S, Yechoor A, Lih FB, Coleman RA. Long-chain acyl-CoA synthetase isoforms differ in preferences for eicosanoid species and long-chain fatty acids. J Lipid Res 2017; 58(5): 884–894

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Meller N, Morgan ME, Wong WP, Altemus JB, Sehayek E. Targeting of acyl-CoA synthetase 5 decreases jejunal fatty acid activation with no effect on dietary long-chain fatty acid absorption. Lipids Health Dis 2013; 12(1): 88

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Klaus C, Schneider U, Hedberg C, Schütz AK, Bernhagen J, Waldmann H, Gassler N, Kaemmerer E. Modulating effects of acyl-CoA synthetase 5-derived mitochondrial Wnt2B palmitoylation on intestinal Wnt activity. World J Gastroenterol 2014; 20(40): 14855–14864

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Mashima T, Sato S, Sugimoto Y, Tsuruo T, Seimiya H. Promotion of glioma cell survival by acyl-CoA synthetase 5 under extracellular acidosis conditions. Oncogene 2009; 28(1): 9–19

    Article  CAS  PubMed  Google Scholar 

  9. Mashima T, Sato S, Okabe S, Miyata S, Matsuura M, Sugimoto Y, Tsuruo T, Seimiya H. Acyl-CoA synthetase as a cancer survival factor: its inhibition enhances the efficacy of etoposide. Cancer Sci 2009; 100(8): 1556–1562

    Article  CAS  PubMed  Google Scholar 

  10. Hartmann F, Sparla D, Tute E, Tamm M, Schneider U, Jeon MK, Kasperk R, Gassler N, Kaemmerer E. Low acyl-CoA synthetase 5 expression in colorectal carcinomas is prognostic for early tumour recurrence. Pathol Res Pract 2017; 213(3): 261–266

    Article  CAS  PubMed  Google Scholar 

  11. Logan CY, Nusse R. The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol 2004; 20(1): 781–810

    Article  CAS  PubMed  Google Scholar 

  12. Yang Y. Wnt signaling in development and disease. Cell Biosci 2012; 2(1): 14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Nusse R, Clevers H. Wnt/β-catenin signaling, disease, and emerging therapeutic modalities. Cell 2017; 169(6): 985–999

    Article  CAS  PubMed  Google Scholar 

  14. Roth J, Zuber C, Park S, Jang I, Lee Y, Kysela KG, Le Fourn V, Santimaria R, Guhl B, Cho JW. Protein N-glycosylation, protein folding, and protein quality control. Mol Cells 2010; 30(6): 497–506

    Article  CAS  PubMed  Google Scholar 

  15. Willert K, Nusse R. Wnt proteins. Cold Spring Harb Perspect Biol 2012; 4(9): a007864

    Article  PubMed  PubMed Central  Google Scholar 

  16. Takada R, Satomi Y, Kurata T, Ueno N, Norioka S, Kondoh H, Takao T, Takada S. Monounsaturated fatty acid modification of Wnt protein: its role in Wnt secretion. Dev Cell 2006; 11(6): 791–801

    Article  CAS  PubMed  Google Scholar 

  17. Hausmann G, Bänziger C, Basler K. Helping Wingless take flight: how WNT proteins are secreted. Nat Rev Mol Cell Biol 2007; 8(4): 331–336

    Article  CAS  PubMed  Google Scholar 

  18. Kaemmerer E, Peuscher A, Reinartz A, Liedtke C, Weiskirchen R, Kopitz J, Gassler N. Human intestinal acyl-CoA synthetase 5 is sensitive to the inhibitor triacsin C. World J Gastroenterol 2011; 17(44): 4883–4889

    Article  PubMed  PubMed Central  Google Scholar 

  19. Mashima T, Oh-hara T, Sato S, Mochizuki M, Sugimoto Y, Yamazaki K, Hamada J, Tada M, Moriuchi T, Ishikawa Y, Kato Y, Tomoda H, Yamori T, Tsuruo T. p53-defective tumors with a functional apoptosome-mediated pathway: a new therapeutic target. J Natl Cancer Inst 2005; 97(10): 765–777

    Article  CAS  PubMed  Google Scholar 

  20. Marino MP, Luce MJ, Reiser J. Small- to large-scale production of lentivirus vectors. Methods Mol Biol 2003; 229: 43–55

    CAS  PubMed  Google Scholar 

  21. Di Veroli GY, Fornari C, Wang D, Mollard S, Bramhall JL, Richards FM, Jodrell DI. Combenefit: an interactive platform for the analysis and visualization of drug combinations. Bioinformatics 2016; 32(18): 2866–2868

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res 2017; 45(W1): W98–W102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Chopard C, Tong PBV, Tóth P, Schatz M, Yezid H, Debaisieux S, Mettling C, Gross A, Pugnière M, Tu A, Strub JM, Mesnard JM, Vitale N, Beaumelle B. Cyclophilin A enables specific HIV-1 Tat palmitoylation and accumulation in uninfected cells. Nat Commun 2018; 9(1): 2251

    Article  PubMed  PubMed Central  Google Scholar 

  24. Klaus C, Kaemmerer E, Reinartz A, Schneider U, Plum P, Jeon MK, Hose J, Hartmann F, Schnölzer M, Wagner N, Kopitz J, Gassler N. TP53 status regulates ACSL5-induced expression of mitochondrial mortalin in enterocytes and colorectal adenocarcinomas. Cell Tissue Res 2014; 357(1): 267–278

    Article  CAS  PubMed  Google Scholar 

  25. Ko PJ, Dixon SJ. Protein palmitoylation and cancer. EMBO Rep 2018; 19(10): e46666

    Article  PubMed  PubMed Central  Google Scholar 

  26. Fhu CW, Ali A. Protein lipidation by palmitoylation and myristoylation in cancer. Front Cell Dev Biol 2021; 9: 673647

    Article  PubMed  PubMed Central  Google Scholar 

  27. MacDonald BT, Tamai K, He X. Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell 2009; 17(1): 9–26

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zhan T, Rindtorff N, Boutros M. Wnt signaling in cancer. Oncogene 2017; 36(11): 1461–1473

    Article  CAS  PubMed  Google Scholar 

  29. Gruszka AM, Valli D, Alcalay M. Wnt signalling in acute myeloid leukaemia. Cells 2019; 8(11): 1403

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wang Y, Krivtsov AV, Sinha AU, North TE, Goessling W, Feng Z, Zon LI, Armstrong SA. The Wnt/beta-catenin pathway is required for the development of leukemia stem cells in AML. Science 2010; 327(5973): 1650–1653

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Willert K, Brown JD, Danenberg E, Duncan AW, Weissman IL, Reya T, Yates JR3rd, Nusse R. Wnt proteins are lipid-modified and can act as stem cell growth factors. Nature 2003; 423(6938): 448–452

    Article  CAS  PubMed  Google Scholar 

  32. Gao X, Hannoush RN. Single-cell imaging of Wnt palmitoylation by the acyltransferase porcupine. Nat Chem Biol 2014; 10(1): 61–68

    Article  CAS  PubMed  Google Scholar 

  33. Nile AH, Hannoush RN. Fatty acylation of Wnt proteins. Nat Chem Biol 2016; 12(2): 60–69

    Article  CAS  PubMed  Google Scholar 

  34. Miranda M, Galli LM, Enriquez M, Szabo LA, Gao X, Hannoush RN, Burrus LW. Identification of the WNT1 residues required for palmitoylation by Porcupine. FEBS Lett 2014; 588(24): 4815–4824

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Gharib E, Nasrinasrabadi P, Zali MR. Development and validation of a lipogenic genes panel for diagnosis and recurrence of colorectal cancer. PLoS One 2020; 15(3): e0229864

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Gharib E, Nasri Nasrabadi P, Reza Zali M. miR-497-5p mediates starvation-induced death in colon cancer cells by targeting acyl-CoA synthetase-5 and modulation of lipid metabolism. J Cell Physiol 2020; 235(7–8): 5570–5589

    Article  CAS  PubMed  Google Scholar 

  37. Zhang L, Lv J, Chen C, Wang X. Roles of acyl-CoA synthetase long-chain family member 5 and colony stimulating factor 2 in inhibition of palmitic or stearic acids in lung cancer cell proliferation and metabolism. Cell Biol Toxicol 2021; 37(1): 15–34

    Article  PubMed  Google Scholar 

  38. Tomoda H, Igarashi K, Cyong JC, Omura S. Evidence for an essential role of long chain acyl-CoA synthetase in animal cell proliferation. Inhibition of long chain acyl-CoA synthetase by triacsins caused inhibition of Raji cell proliferation. J Biol Chem 1991; 266(7): 4214–4219

    Article  CAS  PubMed  Google Scholar 

  39. Mashima T, Sato S, Okabe S, Miyata S, Matsuura M, Sugimoto Y, Tsuruo T, Seimiya H. Acyl-CoA synthetase as a cancer survival factor: its inhibition enhances the efficacy of etoposide. Cancer Sci 2009; 100(8): 1556–1562

    Article  CAS  PubMed  Google Scholar 

  40. Liu F, Kalpage HA, Wang D, Edwards H, Hüttemann M, Ma J, Su Y, Carter J, Li X, Polin L, Kushner J, Dzinic SH, White K, Wang G, Taub JW, Ge Y. Cotargeting of mitochondrial complex I and Bcl-2 shows antileukemic activity against acute myeloid leukemia cells reliant on oxidative phosphorylation. Cancers (Basel) 2020; 12(9): 2400

    Article  CAS  PubMed  Google Scholar 

  41. Valentin R, Grabow S, Davids MS. The rise of apoptosis: targeting apoptosis in hematologic malignancies. Blood 2018; 132(12): 1248–1264

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Prof. Guido Marcucci of the City of Hope Medical Center and Beckman Research Institute, Duarte, California, USA, for providing us the THP-1-luciferase cell line. This work was supported by the key international cooperation projects of the National Natural Science Foundation of China (No. 81820108004), the major projects of the Zhejiang Provincial Department of Science and Technology (No. 2021C03123), and the Pediatric Leukemia Diagnosis and Therapeutic Technology Research Center of Zhejiang Province (No. JBZX-201904).

Author information

Author notes

  1. Wenle Ye and Jinghan Wang contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology, The First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, 310003, China

    Wenle Ye, Jinghan Wang, Jiansong Huang, Xia Li, Xin Huang, Fenglin Li, Shujuan Huang, Jiajia Pan, Jingrui Jin, Qing Ling, Yungui Wang, Jie Sun & Jie Jin

  2. Key Laboratory of Hematopoietic Malignancies, Diagnosis and Treatment, Hangzhou, 310009, China

    Wenle Ye, Jinghan Wang, Jiansong Huang, Xia Li, Xin Huang, Fenglin Li, Shujuan Huang, Jiajia Pan, Jingrui Jin, Qing Ling, Yungui Wang, Jie Sun & Jie Jin

  3. Research Centre, Centre hospitalier de l’Université de Montréal (CRCHUM), Montreal, Quebec, H2L 4M1, Canada

    Xiao He

  4. Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, 310006, China

    Zhixin Ma

  5. Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China

    Yongping Yu

  6. Cancer Center, Zhejiang University, Hangzhou, 310058, China

    Jie Jin

Authors
  1. Wenle Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jinghan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jiansong Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiao He
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhixin Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xia Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xin Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Fenglin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Shujuan Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jiajia Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jingrui Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Qing Ling
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Yungui Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Yongping Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Jie Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Jie Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Jie Sun or Jie Jin.

Ethics declarations

Wenle Ye, Jinghan Wang, Jiansong Huang, Xiao He, Zhixin Ma, Xia Li, Xin Huang, Fenglin Li, Shujuan Huang, Jiajia Pan, Jingrui Jin, Qing Ling, Yungui Wang, Yongping Yu, Jie Sun, and Jie Jin declare no conflict of interest. This study was approved by the ethics committee of the First Affiliated Hospital of Zhejiang University. All procedures followed were in accordance with the ethical standards of the responsible committees on human experimentation (institutional and national) and with the Helsinki Declaration of 1975 as revised in 2000. Informed consents were obtained from all patients participating in this study. All institutional and national guidelines for the care and use of laboratory animals were also followed.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ye, W., Wang, J., Huang, J. et al. ACSL5, a prognostic factor in acute myeloid leukemia, modulates the activity of Wnt/β-catenin signaling by palmitoylation modification. Front. Med. 17, 685–698 (2023). https://doi.org/10.1007/s11684-022-0942-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11684-022-0942-1

Keywords

Search

Navigation