CTCF-activated FUCA1 functions as a tumor suppressor by promoting autophagy flux and serum α-L-fucosidase serves as a potential biomarker for prognosis in ccRCC.
Autophagy
CTCF
Clear cell renal cell carcinoma
FUCA1
α-L-fucosidase
Journal
Cancer cell international
ISSN: 1475-2867
Titre abrégé: Cancer Cell Int
Pays: England
ID NLM: 101139795
Informations de publication
Date de publication:
28 Sep 2024
28 Sep 2024
Historique:
received:
28
04
2024
accepted:
05
09
2024
medline:
29
9
2024
pubmed:
29
9
2024
entrez:
28
9
2024
Statut:
epublish
Résumé
Notably, clear cell renal cell carcinoma (ccRCC) is characterized by a distinct metabolic tumor phenotype that involves the reprogramming of multiple metabolic pathways. Although there is increasing evidence linking FUCA1 to malignancies, its specific role and downstream signaling pathways in ccRCC remain poorly understood. Here we found that FUCA1 expression was significantly downregulated in ccRCC tissues, which also predicts poor prognosis of ccRCCpatients. Moreover, enhancing FUCA1 expression resulted in reduced invasion and migration of ccRCC cells, further indicating its protective role. CHIP-qPCR and luciferase assays showed that CTCF was an upstream transcription factor of FUCA1 and could reverse the effects caused by FUCA1 inactivation. The change in FUCA1 led to changes in the results of various autophagy-related proteins and the mRFP-GFP-LC3 dual fluorescence system, indicating that it may play a role in the fusion stage of autophagy. Protein-protein interaction analysis revealed that FUCA2 exhibited the closest interaction with FUCA1 and strongly predicted the prognosis of ccRCC patients. Additionally, serum AFU encoded by FUCA2 could serve as a valuable predictor for survival in ccRCC patients. FUCA1 suppresses invasion and migration of ccRCC cells, with its activity being modulated by CTCF. FUCA1 regulates the autophagy process in ccRCC cells by influencing the fusion between autophagosomes and lysosomes. FUCA2 shares similarities with FUCA1, and elevated serum AFU levels along with increased expression of FUCA2 are indicative of a favorable prognosis in ccRCC.
Identifiants
pubmed: 39342260
doi: 10.1186/s12935-024-03502-2
pii: 10.1186/s12935-024-03502-2
doi:
Types de publication
Journal Article
Langues
eng
Pagination
327Subventions
Organisme : National Natural Science Foundation of China
ID : 82102999
Informations de copyright
© 2024. The Author(s).
Références
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69:734.
doi: 10.3322/caac.21551
Büttner FA, Winter S, Stühler V, Rausch S, Hennenlotter J, Füssel S, et al. A novel molecular signature identifies mixed subtypes in renal cell carcinomawith poor prognosis and independent response to immunotherapy. Genome Med. 2022;14:105.
pubmed: 36109798
pmcid: 9476269
doi: 10.1186/s13073-022-01105-y
Chow WH, Dong LM, Devesa SS. Epidemiology and risk factors for kidney cancer. Nat Rev Urol. 2010;7:245–57.
pubmed: 20448658
pmcid: 3012455
doi: 10.1038/nrurol.2010.46
Li Z, Xu H, Yu L, Wang J, Meng Q, Mei H, et al. Patient-derived renal cell carcinoma organoids for personalized cancer therapy. Clin Transl Med. 2022;12:e970.
pubmed: 35802820
pmcid: 9270001
doi: 10.1002/ctm2.970
Motzer RJ, Bacik J, Mazumdar M. Prognostic factors for survival of patients with stage IV renal cell carcinoma: memorial sloan-kettering cancer center experience. Clin Cancer Res. 2004;10:s6302–3.
doi: 10.1158/1078-0432.CCR-040031
Moch H, Cubilla AL, Humphrey PA, Reuter VE, Ulbright TM. The 2016 WHO classification of Tumours of the urinary system and male genital organs-Part A: renal, Penile, and testicular tumours. Eur Urol. 2016;70:93–105.
pubmed: 26935559
doi: 10.1016/j.eururo.2016.02.029
Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, et al. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019;380:1116–27.
pubmed: 30779529
doi: 10.1056/NEJMoa1816714
Ljungberg B, Albiges L, Abu-Ghanem Y, Bensalah K, Dabestani S, Fernández-Pello S, et al. European Association of Urology Guidelines on Renal Cell Carcinoma: the 2019 Update. Eur Urol. 2019;75:799–810.
pubmed: 30803729
doi: 10.1016/j.eururo.2019.02.011
Hakomori S. Glycosylation defining cancer malignancy: new wine in an old bottle. Proc Natl Acad Sci U S A. 2002;99:10231–3.
pubmed: 12149519
pmcid: 124893
doi: 10.1073/pnas.172380699
Meany DL, Chan DW. Aberrant glycosylation associated with enzymes as cancer biomarkers. Clin Proteom. 2011;8:7.
doi: 10.1186/1559-0275-8-7
Ezawa I, Sawai Y, Kawase T, Okabe A, Tsutsumi S, Ichikawa H, et al. Novel p53 target gene FUCA1 encodes a fucosidase and regulates growth and survival of cancer cells. Cancer Sci. 2016;107:734–45.
pubmed: 26998741
pmcid: 4968591
doi: 10.1111/cas.12933
Fu J, Guo Q, Feng Y, Cheng P, Wu A, et al. Dual role of fucosidase in cancers and its clinical potential. J Cancer. 2022;13:3121–32.
pubmed: 36046653
pmcid: 9414016
doi: 10.7150/jca.75840
Saleh-Gohari N, Saeidi K, Zeighaminejad R. A novel homozygous frameshift mutation in the FUCA1 gene causes both severe and mild fucosidosis. J Clin Pathol. 2018;71:821–4.
pubmed: 29588375
doi: 10.1136/jclinpath-2018-205074
Xiao Y, Jiang X, Yin K, Miao T, Lu H, Wang W, et al. USP35 promotes cell proliferation and chemotherapeutic resistance through stabilizing FUCA1 in colorectal cancer. Oncogenesis. 2023;12:12.
pubmed: 36864055
doi: 10.1038/s41389-023-00458-2
Yu Y, Lin XY, Zhang SC, Guo MQ, Ma XT, Wang K. Association and prognostic significance of alpha-L-fucosidase-1 and matrix metalloproteinase 9 expression in esophageal squamous cell carcinoma. World J Gastrointest Oncol. 2022;14:498–510.
pubmed: 35317318
pmcid: 8919000
doi: 10.4251/wjgo.v14.i2.498
Xu L, Li Z, Song S, Chen Q, Mo L, Wang C, et al. Downregulation of α-l-fucosidase 1 suppresses glioma progression by enhancing autophagy and inhibiting macrophage infiltration. Cancer Sci. 2020;111:2284–96.
pubmed: 32314457
pmcid: 7385365
doi: 10.1111/cas.14427
Tsuchida N, Ikeda MA, Ιshino Υ, Grieco M, Vecchio G. FUCA1 is induced by wild-type p53 and expressed at different levels in thyroid cancers depending on p53 status. Int J Oncol. 2017;50:2043–8.
pubmed: 28440416
doi: 10.3892/ijo.2017.3968
Phillips JE, Corces VG. CTCF: master weaver of the genome. Cell. 2009;137:1194–211.
pubmed: 19563753
pmcid: 3040116
doi: 10.1016/j.cell.2009.06.001
Bell AC, West AG, Felsenfeld G. The protein CTCF is required for the enhancer blocking activity of vertebrate insulators. Cell. 1999;98:387–96.
pubmed: 10458613
doi: 10.1016/S0092-8674(00)81967-4
Dixon JR, Selvaraj S, Yue F, Kim A, Li Y, Shen Y, et al. Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature. 2012;485:376–80.
pubmed: 22495300
pmcid: 3356448
doi: 10.1038/nature11082
Phillips-Cremins JE, Corces VG. Chromatin insulators: linking genome organization to cellular function. Mol Cell. 2013;50:461–74.
pubmed: 23706817
pmcid: 3670141
doi: 10.1016/j.molcel.2013.04.018
Vostrov V, Quitschke AA. Evidence for a role in transcriptional the zinc finger protein CTCF binds to the APBbeta domain of the amyloid beta-protein precursor promoter activation. J Biol Chem. 1997;272:33353–9.
pubmed: 9407128
doi: 10.1074/jbc.272.52.33353
Tang Z, Luo OJ, Li X, Zheng M, Zhu JJ, Szalaj P, et al. CTCF-Mediated human 3D Genome Architecture reveals chromatin topology for transcription. Cell. 2015;163:1611–27.
pubmed: 26686651
pmcid: 4734140
doi: 10.1016/j.cell.2015.11.024
Debnath J, Gammoh N, Ryan KM. Autophagy and autophagy-related pathways in cancer. Nat Rev Mol Cell Biol. 2023;24:560–75.
pubmed: 36864290
doi: 10.1038/s41580-023-00585-z
Yue Z, Jin S, Yang C, Levine AJ, Heintz N. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci U S A. 2003;100:15077–82.
pubmed: 14657337
pmcid: 299911
doi: 10.1073/pnas.2436255100
Choi KS. Autophagy and cancer. Exp Mol Med. 2012;44:109–20.
pubmed: 22257886
pmcid: 3296807
doi: 10.3858/emm.2012.44.2.033
Qu X, Yu J, Bhagat G, Furuya N, Hibshoosh H, Troxel A, et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest. 2003;112:1809–20.
pubmed: 14638851
pmcid: 297002
doi: 10.1172/JCI20039
Di Malta C, Siciliano D, Calcagni A, Monfregola J, Punzi S, Pastore N, et al. Transcriptional activation of RagD GTPase controls mTORC1 and promotes cancer growth. Science. 2017;356:1188–92.
pubmed: 28619945
pmcid: 5730647
doi: 10.1126/science.aag2553
Deng F, Ma YX, Liang L, Zhang P, Feng J. The pro-apoptosis effect of sinomenine in renal carcinoma via inducing autophagy through inactivating PI3K/AKT/mTOR pathway. Biomed Pharmacother. 2018;97:1269–74.
pubmed: 29145153
doi: 10.1016/j.biopha.2017.11.064
Verma SP, Agarwal A, Das P. Sodium butyrate induces cell death by autophagy and reactivates a tumor suppressor gene DIRAS1 in renal cell carcinoma cell line UOK146. Vitro Cell Dev Biol Anim. 2018;54:295–303.
doi: 10.1007/s11626-018-0239-5
Zhang Y, Fan Y, Huang S, Wang G, Han R, Lei F, et al. Thymoquinone inhibits the metastasis of renal cell cancer cells by inducing autophagy via AMPK/mTOR signaling pathway. Cancer Sci. 2018;109:3865–73.
pubmed: 30259603
pmcid: 6272120
doi: 10.1111/cas.13808
Warde-Farley D, Donaldson SL, Comes O, Zuberi K, Badrawi R, Chao P, et al. The GeneMANIA prediction server: biological network integration for gene prioritization and predicting gene function. Nucleic Acids Res. 2010;38:214–20.
doi: 10.1093/nar/gkq537
Ferreira PMP, Sousa RWR, Ferreira JRO, Militão GCG, Bezerra DP. Chloroquine and hydroxychloroquine in antitumor therapies based on autophagy-related mechanisms. Pharmacol Res. 2021;168:105582.
pubmed: 33775862
doi: 10.1016/j.phrs.2021.105582
Zhang X, Sun Y, Ma Y, Gao C, Zhang Y, Yang X. Tumor-associated M2 macrophages in the immune microenvironment influence the progression of renal clear cell carcinoma by regulating M2 macrophage-associated genes. Front Oncol. 2023;13:1157861.
pubmed: 37361571
pmcid: 10285481
doi: 10.3389/fonc.2023.1157861
Zhang C, Liu J, Chao F, Wang S, Li D, Han D, et al. Alpha-L-Fucosidase has diagnostic value in prostate Cancer with Gray-Zone PSA and inhibits Cancer Progression via regulating glycosylation. Front Oncol. 2021;11:742354.
pubmed: 34881177
pmcid: 8645591
doi: 10.3389/fonc.2021.742354
Otero-Estévez O, Martínez-Fernández M, Vázquez-Iglesias L, de la Páez M, Rodríguez-Berrocal FJ, Martínez-Zorzano VS, et al. Decreased expression of alpha-L-fucosidase gene FUCA1 in human colorectal tumors. Int J Mol Sci. 2013;14:16986–98.
pubmed: 23965968
pmcid: 3759947
doi: 10.3390/ijms140816986
Baudot AD, Crighton D, O’Prey J, Somers J, Sierra Gonzalez P, Ryan KM. p53 directly regulates the glycosidase FUCA1 to promote chemotherapy-induced cell death. Cell Cycle. 2016;15:2299–308.
pubmed: 27315169
pmcid: 5004703
doi: 10.1080/15384101.2016.1191714
Wang Y, Yan K, Lin J, Li J, Bi J. Macrophage M2 co-expression factors correlate with the Immune Microenvironment and Predict Outcome of Renal Clear Cell Carcinoma. Front Genet. 2021;12:615655.
pubmed: 33692827
pmcid: 7938896
doi: 10.3389/fgene.2021.615655
Zhong A, Chen T, Xing Y, Pan X, Shi M. FUCA2 is a prognostic biomarker and correlated with an immunosuppressive microenvironment in Pan-cancer. Front Immunol. 2021;12:758648.
pubmed: 34745134
pmcid: 8565374
doi: 10.3389/fimmu.2021.758648
Segueni J, Noordermeer D. CTCF: a misguided jack-of-all-trades in cancer cells. Comput Struct Biotechnol J. 2022;20:2685–98.
pubmed: 35685367
pmcid: 9166472
doi: 10.1016/j.csbj.2022.05.044
Bailey CG, Metierre C, Feng Y, Baidya K, Filippova GN, Loukinov DI et al. CTCF expression is essential for somatic cell viability and Protection Against Cancer. Int J Mol Sci. 2018; 19.
Docquier F, Farrar D, D’Arcy V, Chernukhin I, Robinson AF, Loukinov D, et al. Heightened expression of CTCF in breast cancer cells is associated with resistance to apoptosis. Cancer Res. 2005;65:5112–22.
pubmed: 15958555
doi: 10.1158/0008-5472.CAN-03-3498
Zhang B, Zhang Y, Zou X, Chan AW, Zhang R, Lee TK, et al. The CCCTC-binding factor (CTCF)-forkhead box protein M1 axis regulates tumour growth and metastasis in hepatocellular carcinoma. J Pathol. 2017;243:418–30.
pubmed: 28862757
pmcid: 5725705
doi: 10.1002/path.4976
Marshall AD, Bailey CG, Rasko JE. CTCF and BORIS in genome regulation and cancer. Curr Opin Genet Dev. 2014;24:8–15.
pubmed: 24657531
doi: 10.1016/j.gde.2013.10.011
Nakahashi H, Kieffer Kwon KR, Resch W, Vian L, Dose M, Stavreva D, et al. A genome-wide map of CTCF multivalency redefines the CTCF code. Cell Rep. 2013;3:1678–89.
pubmed: 23707059
pmcid: 3770538
doi: 10.1016/j.celrep.2013.04.024
Li X, He S, Ma B. Autophagy and autophagy-related proteins in cancer. Mol Cancer. 2020;19:12.
pubmed: 31969156
pmcid: 6975070
doi: 10.1186/s12943-020-1138-4
Dell’Atti L, Bianchi N, Aguiari G. New therapeutic interventions for kidney carcinoma: looking to the future. Cancers (Basel). 2022; 14.
Xu Y, Li L, Yang W, Zhang K, Zhang Z, Yu C, et al. TRAF2 promotes M2-polarized tumor-associated macrophage infiltration, angiogenesis and cancer progression by inhibiting autophagy in clear cell renal cell carcinoma. J Exp Clin Cancer Res. 2023;42:159.
pubmed: 37415241
pmcid: 10324183
doi: 10.1186/s13046-023-02742-w
Xu Y, Zhou J, Li L, Yang W, Zhang Z, Zhang K, et al. FTO-mediated autophagy promotes progression of clear cell renal cell carcinoma via regulating SIK2 mRNA stability. Int J Biol Sci. 2022;18:5943–62.
pubmed: 36263177
pmcid: 9576516
doi: 10.7150/ijbs.77774