ATP Citrate Lyase is a General Tumour Biomarker and Contributes to the Development of Cutaneous Squamous Cell Carcinoma
DOI:
https://doi.org/10.2340/actadv.v104.23805Keywords:
ATP citrate lyase, biomarker, skin neoplasmsAbstract
ATP citrate lyase, the first rate-limiting enzyme in de novo lipogenesis, plays a crucial role in tumour progression. This study explores ATP citrate lyase’s potential as a tumour biomarker and its role in cutaneous squamous cell carcinoma. ATP citrate lyase expression patterns were analysed using TCGA and TIMER databases, and patient skin specimens were collected for immunohistochemistry to determine ATP citrate lyase levels. Cell proliferation, cell cycle, apoptosis, and c-Myc expression were assessed in A431 and SCL-1 cells. Stable cell lines with reduced ATP citrate lyase expression were obtained and subcutaneously implanted into nude mice to evaluate in vivo tumour growth. Ki67, c-Myc expression and TUNEL staining were analysed in subcutaneous tumours. ATP citrate lyase exhibited upregulation in various tumours, and showed significant associations with prognosis and immune infiltrate. Moreover, ATP citrate lyase was highly expressed in cutaneous squamous cell carcinoma. After ATP citrate lyase silencing, cutaneous squamous cell carcinoma cell growth decelerated, the cell cycle halted, cell apoptosis increased, and c-Myc expression decreased. Animal experiments revealed that, following ATP citrate lyase knockdown, tumour tissue growth slowed down, and there was a reduction in Ki-67 and c-Myc expression, accompanied by enhanced TUNEL staining. In conclusion, ATP citrate lyase may serve as a tumour biomarker. It is highly expressed in cutaneous squamous cell carcinoma and may serve as a therapeutic target.
Downloads
References
Corchado-Cobos R, Garcia-Sancha N, Gonzalez-Sarmiento R, Perez-Losada J, Canueto J. Cutaneous squamous cell carcinoma: from biology to therapy. Int J Mol Sci 2020; 21: 2956.
https://doi.org/10.3390/ijms21082956 DOI: https://doi.org/10.3390/ijms21082956
Chang MS, Azin M, Demehri S. Cutaneous squamous cell carcinoma: the frontier of cancer immunoprevention. Annu Rev Pathol 2022; 17: 101-119.
https://doi.org/10.1146/annurev-pathol-042320-120056 DOI: https://doi.org/10.1146/annurev-pathol-042320-120056
Manyam BV, Garsa AA, Chin RI, Reddy CA, Gastman B, Thorstad W, et al. A multi-institutional comparison of outcomes of immunosuppressed and immunocompetent patients treated with surgery and radiation therapy for cutaneous squamous cell carcinoma of the head and neck. Cancer 2017; 123: 2054-2060.
https://doi.org/10.1002/cncr.30601 DOI: https://doi.org/10.1002/cncr.30601
Menendez JA, Lupu R. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer 2007; 7: 763-777.
https://doi.org/10.1038/nrc2222 DOI: https://doi.org/10.1038/nrc2222
Rohrig F, Schulze A. The multifaceted roles of fatty acid synthesis in cancer. Nat Rev Cancer 2016; 16: 732-749.
https://doi.org/10.1038/nrc.2016.89 DOI: https://doi.org/10.1038/nrc.2016.89
Ascencao K, Dilek N, Augsburger F, Panagaki T, Zuhra K, Szabo C. Pharmacological induction of mesenchymal-epithelial transition via inhibition of H2S biosynthesis and consequent suppression of ACLY activity in colon cancer cells. Pharmacol Res 2021; 165: 105393.
https://doi.org/10.1016/j.phrs.2020.105393 DOI: https://doi.org/10.1016/j.phrs.2020.105393
Adorno-Cruz V, Hoffmann AD, Liu X, Dashzeveg NK, Taftaf R, Wray B, et al. ITGA2 promotes expression of ACLY and CCND1 in enhancing breast cancer stemness and metastasis. Genes Dis 2021; 8: 493-508.
https://doi.org/10.1016/j.gendis.2020.01.015 DOI: https://doi.org/10.1016/j.gendis.2020.01.015
Zhang C, Liu J, Huang G, Zhao Y, Yue X, Wu H, et al. Cullin3-KLHL25 ubiquitin ligase targets ACLY for degradation to inhibit lipid synthesis and tumor progression. Genes Dev 2016; 30: 1956-1970.
https://doi.org/10.1101/gad.283283.116 DOI: https://doi.org/10.1101/gad.283283.116
Dai M, Yang B, Chen J, Liu F, Zhou Y, Zhou Y, et al. Nuclear-translocation of ACLY induced by obesity-related factors enhances pyrimidine metabolism through regulating histone acetylation in endometrial cancer. Cancer Lett 2021; 513: 36-49.
https://doi.org/10.1016/j.canlet.2021.04.024 DOI: https://doi.org/10.1016/j.canlet.2021.04.024
Thorsson V, Gibbs DL, Brown SD, Wolf D, Bortone DS, Ou Yang TH, et al. The immune landscape of cancer. Immunity 2018; 48: 812-830 e814.
Li T, Fan J, Wang B, Traugh N, Chen Q, Liu JS, et al. TIMER: A web server for comprehensive analysis of tumor-infiltrating immune cells. Cancer Res 2017; 77: e108-e110.
https://doi.org/10.1158/0008-5472.CAN-17-0307 DOI: https://doi.org/10.1158/0008-5472.CAN-17-0307
Pinheiro C, Longatto-Filho A, Scapulatempo C, Ferreira L, Martins S, Pellerin L, et al. Increased expression of monocarboxylate transporters 1, 2, and 4 in colorectal carcinomas. Virchows Arch 2008; 452: 139-146.
https://doi.org/10.1007/s00428-007-0558-5 DOI: https://doi.org/10.1007/s00428-007-0558-5
Jia J, Li C, Luo S, Liu-Smith F, Yang J, Wang X, et al. Yes-associated protein contributes to the development of human cutaneous squamous cell carcinoma via activation of RAS. J Invest Dermatol 2016; 136: 1267-1277.
https://doi.org/10.1016/j.jid.2016.02.005 DOI: https://doi.org/10.1016/j.jid.2016.02.005
Johansen C. Generation and culturing of primary human keratinocytes from adult skin. J Vis Exp 2017; 130: 56863.
https://doi.org/10.3791/56863-v DOI: https://doi.org/10.3791/56863-v
Li C, Xiao L, Jia J, Li F, Wang X, Duan Q, et al. Cornulin is induced in psoriasis lesions and promotes keratinocyte proliferation via phosphoinositide 3-kinase/Akt pathways. J Invest Dermatol 2019; 139: 71-80.
https://doi.org/10.1016/j.jid.2018.06.184 DOI: https://doi.org/10.1016/j.jid.2018.06.184
Beckner ME, Fellows-Mayle W, Zhang Z, Agostino NR, Kant JA, Day BW, et al. Identification of ATP citrate lyase as a positive regulator of glycolytic function in glioblastomas. Int J Cancer 2010; 126: 2282-2295.
https://doi.org/10.1002/ijc.24918 DOI: https://doi.org/10.1002/ijc.24918
Migita T, Narita T, Nomura K, Miyagi E, Inazuka F, Matsuura M, et al. ATP citrate lyase: activation and therapeutic implications in non-small cell lung cancer. Cancer Res 2008; 68: 8547-8554.
https://doi.org/10.1158/0008-5472.CAN-08-1235 DOI: https://doi.org/10.1158/0008-5472.CAN-08-1235
Teng L, Chen Y, Cao Y, Wang W, Xu Y, Wang Y, et al. Overexpression of ATP citrate lyase in renal cell carcinoma tissues and its effect on the human renal carcinoma cells in vitro. Oncol Lett 2018; 15: 6967-6974.
https://doi.org/10.3892/ol.2018.8211 DOI: https://doi.org/10.3892/ol.2018.8211
Huang SS, Tsai CH, Kuo CY, Li YS, Cheng SP. ACLY inhibitors induce apoptosis and potentiate cytotoxic effects of sorafenib in thyroid cancer cells. Endocrine 2022; 78: 85-94.
https://doi.org/10.1007/s12020-022-03124-6 DOI: https://doi.org/10.1007/s12020-022-03124-6
Wang J, Ye W, Yan X, Guo Q, Ma Q, Lin F, et al. Low expression of ACLY associates with favorable prognosis in acute myeloid leukemia. J Transl Med 2019; 17: 149.
https://doi.org/10.1186/s12967-019-1884-5 DOI: https://doi.org/10.1186/s12967-019-1884-5
Osugi J, Yamaura T, Muto S, Okabe N, Matsumura Y, Hoshino M, et al. Prognostic impact of the combination of glucose transporter 1 and ATP citrate lyase in node-negative patients with non-small lung cancer. Lung Cancer 2015; 88: 310-318.
https://doi.org/10.1016/j.lungcan.2015.03.004 DOI: https://doi.org/10.1016/j.lungcan.2015.03.004
Zhang Q, Yin X, Pan Z, Cao Y, Han S, Gao G, et al. Identification of potential diagnostic and prognostic biomarkers for prostate cancer. Oncol Lett 2019; 18: 4237-4245.
https://doi.org/10.3892/ol.2019.10765 DOI: https://doi.org/10.3892/ol.2019.10765
Xiang W, Lv H, Xing F, Sun X, Ma Y, Wu L, et al. Inhibition of ACLY overcomes cancer immunotherapy resistance via polyunsaturated fatty acids peroxidation and cGAS-STING activation. Sci Adv 2023; 9: eadi2465.
https://doi.org/10.1126/sciadv.adi2465 DOI: https://doi.org/10.1126/sciadv.adi2465
Icard P, Wu Z, Fournel L, Coquerel A, Lincet H, Alifano M. ATP citrate lyase: a central metabolic enzyme in cancer. Cancer Lett 2020; 471: 125-134.
https://doi.org/10.1016/j.canlet.2019.12.010 DOI: https://doi.org/10.1016/j.canlet.2019.12.010
Guo W, Ma J, Yang Y, Guo S, Zhang W, Zhao T, et al. ATP-citrate lyase epigenetically potentiates oxidative phosphorylation to promote melanoma growth and adaptive resistance to MAPK inhibition. Clin Cancer Res 2020; 26: 2725-2739.
https://doi.org/10.1158/1078-0432.CCR-19-1359 DOI: https://doi.org/10.1158/1078-0432.CCR-19-1359
Hatzivassiliou G, Zhao F, Bauer DE, Andreadis C, Shaw AN, Dhanak D, et al. ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell 2005; 8: 311-321.
https://doi.org/10.1016/j.ccr.2005.09.008 DOI: https://doi.org/10.1016/j.ccr.2005.09.008
Hanai J, Doro N, Sasaki AT, Kobayashi S, Cantley LC, Seth P, et al. Inhibition of lung cancer growth: ATP citrate lyase knockdown and statin treatment leads to dual blockade of mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K)/AKT pathways. J Cell Physiol 2012; 227: 1709-1720.
https://doi.org/10.1002/jcp.22895 DOI: https://doi.org/10.1002/jcp.22895
Stine ZE, Walton ZE, Altman BJ, Hsieh AL, Dang CV. MYC, metabolism, and cancer. Cancer Discov 2015; 5: 1024-1039.
https://doi.org/10.1158/2159-8290.CD-15-0507 DOI: https://doi.org/10.1158/2159-8290.CD-15-0507
Dhanasekaran R, Deutzmann A, Mahauad-Fernandez WD, Hansen AS, Gouw AM, Felsher DW. The MYC oncogene: the grand orchestrator of cancer growth and immune evasion. Nat Rev Clin Oncol 2022; 19: 23-36.
https://doi.org/10.1038/s41571-021-00549-2 DOI: https://doi.org/10.1038/s41571-021-00549-2
Additional Files
Published
How to Cite
License
Copyright (c) 2024 Ruiting Luo, Yingjian Huang, Ruimin Bai, Meng Liu, Liang Sun, Xiaofei Wang, Yan Zheng
![Creative Commons License](http://i.creativecommons.org/l/by-nc/4.0/88x31.png)
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
All digitalized ActaDV contents is available freely online. The Society for Publication of Acta Dermato-Venereologica owns the copyright for all material published until volume 88 (2008) and as from volume 89 (2009) the journal has been published fully Open Access, meaning the authors retain copyright to their work.
Unless otherwise specified, all Open Access articles are published under CC-BY-NC licences, allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material for non-commercial purposes, provided proper attribution to the original work.