Downregulating FGGY carbohydrate kinase domain containing promotes cell senescence by activating the p53/p21 signaling pathway in colorectal cancer

Liu,Liya; Wu,Meizhu; Chen,Youqin; Cheng,Ying; Liu,Sijia; Zhang,Xinran; Xie,Qiurong; Cao,Liujing; Wei,Lihui; Fang,Yi; Jafri,Anjum; Sferra,Thomas J.; Shen,Aling; Li,Li

doi:10.3892/ijmm.2025.5522

Downregulating FGGY carbohydrate kinase domain containing promotes cell senescence by activating the p53/p21 signaling pathway in colorectal cancer

Authors:
- Liya Liu
- Meizhu Wu
- Youqin Chen
- Ying Cheng
- Sijia Liu
- Xinran Zhang
- Qiurong Xie
- Liujing Cao
- Lihui Wei
- Yi Fang
- Anjum Jafri
- Thomas J. Sferra
- Aling Shen
- Li Li
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Affiliations: Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China, Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China, Department of Pediatrics, Case Western Reserve University School of Medicine, Rainbow Babies and Children's Hospital, Cleveland, OH 44106, USA, Department of Genetics and Genome Sciences, Histology Core, Case Western Reserve University, Cleveland, OH 44106, USA, Shengli Clinical College, Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
Published online on: March 20, 2025 https://doi.org/10.3892/ijmm.2025.5522
Article Number: 81
Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Carbohydrate kinases serve an oncogenic role in several types of cancer; however, the function of FGGY carbohydrate kinase domain containing (FGGY) in colorectal cancer (CRC) remains unknown. The present study investigated the function and possible molecular mechanisms of FGGY in CRC. The results showed that elevated levels of FGGY mRNA and protein were observed in CRC tissues, and a higher expression of FGGY was associated with advanced N stage and reduced overall survival time in patients with CRC. Silencing FGGY inhibited the viability of CRC cells by inducing cell cycle arrest and promoting apoptosis in vitro, thereby attenuating tumor growth in a xenograft mouse model. FGGY knockdown also enriched the senescence‑associated heterochromatin foci (SAHF) pathway and p53 pathway, as further confirmed by enhancing senescence‑associated β‑galactosidase (SA‑β‑gal) activity, with increased levels of SAHF‑associated proteins HP1γ and trimethylation of H3K9 (H3k9me3) in CRC cells, as well as upregulation of p53 and its downstream protein p21. Furthermore, p53 knockout rescued FGGY knockdown‑mediated reductions in cell viability, SA‑β‑gal activity, and the levels of HP1γ and H3k9me3 in CRC cells. These findings indicated that FGGY could act as a newly identified potential oncogene in CRC, partially through regulating the p53/p21 signaling pathway and altering cell senescence.

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1	Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A and Bray F: Cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 71:209–249. 2021. View Article : Google Scholar : PubMed/NCBI
2	Siegel RL, Miller KD, Wagle NS and Jemal A: Cancer statistics, 2023. CA cancer J Clin. 73:17–48. 2023. View Article : Google Scholar : PubMed/NCBI
3	Ladabaum U, Dominitz JA, Kahi C and Schoen RE: Strategies for colorectal cancer screening. Gastroenterology. 158:418–432. 2020. View Article : Google Scholar
4	Kanth P and Inadomi JM: Screening and prevention of colorectal cancer. BMJ. 374:n18552021. View Article : Google Scholar : PubMed/NCBI
5	Shen A, Chen Y, Liu L, Huang Y, Chen H, Qi F, Lin J, Shen Z, Wu X, Wu M, et al: EBF1-mediated upregulation of ribosome assembly factor PNO1 contributes to cancer progression by negatively regulating the p53 signaling pathway. Cancer Res. 79:2257–2270. 2019. View Article : Google Scholar : PubMed/NCBI
6	Zhang Y, Zagnitko O, Rodionova I, Osterman A and Godzik A: The FGGY carbohydrate kinase family: Insights into the evolution of functional specificities. PLoS Comput Biol. 7:e10023182011. View Article : Google Scholar
7	Omelchenko MV, Makarova KS, Wolf YI, Rogozin IB and Koonin EV: Non-homologous isofunctional enzymes: A systematic analysis of alternative solutions in enzyme evolution. Biol Direct. 5:312010. View Article : Google Scholar : PubMed/NCBI
8	Daoud H, Valdmanis PN, Dion PA and Rouleau GA: Analysis of DPP6 and FGGY as candidate genes for amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 11:389–391. 2010. View Article : Google Scholar
9	Van Es MA, Van Vught PW, Veldink JH, Andersen PM, Birve A, Lemmens R, Cronin S, Van Der Kooi AJ, De Visser M, Schelhaas HJ, et al: Analysis of FGGY as a risk factor for sporadic amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 10:441–447. 2009. View Article : Google Scholar : PubMed/NCBI
10	Taylor JA, Shioda K, Mitsunaga S, Yawata S, Angle BM, Nagel SC, Vom Saal FS and Shioda T: Prenatal exposure to bisphenol a disrupts naturally occurring bimodal dna methylation at proximal promoter of fggy, an obesity-relevant gene encoding a carbohydrate kinase, in gonadal white adipose tissues of cd-1 mice. Endocrinology. 159:779–794. 2018. View Article : Google Scholar :
11	Zhang R, Zhang F, Sun Z, Liu P, Zhang X, Ye Y, Cai B, Walsh MJ, Ren X, Hao X, et al: LINE-1 retrotransposition promotes the development and progression of lung squamous cell carcinoma by disrupting the tumor-suppressor gene fggy. Cancer Res. 79:4453–4465. 2019.PubMed/NCBI
12	Sun Z, Zhang R, Zhang X, Sun Y, Liu P, Francoeur N, Han L, Lam WY, Yi Z, Sebra R, et al: LINE-1 promotes tumorigenicity and exacerbates tumor progression via stimulating metabolism reprogramming in non-small cell lung cancer. Mol Cancer. 21:1472022.PubMed/NCBI
13	Skrzypczak M, Goryca K, Rubel T, Paziewska A, Mikula M, Jarosz D, Pachlewski J, Oledzki J and Ostrowski J: Modeling oncogenic signaling in colon tumors by multidirectional analyses of microarray data directed for maximization of analytical reliability. PLoS One. 5:e130912010.PubMed/NCBI
14	Tomczak K, Czerwińska P and Wiznerowicz M: The cancer genome atlas (TCGA): An immeasurable source of knowledge. Contemp Oncol (Pozn). 19:A68–A77. 2015.PubMed/NCBI
15	Marisa L, de Reyniès A, Duval A, Selves J, Gaub MP, Vescovo L, Etienne-Grimaldi MC, Schiappa R, Guenot D, Ayadi M, et al: Gene expression classification of colon cancer into molecular subtypes: Characterization, validation, and prognostic value. PLoS Med. 10:e10014532013.PubMed/NCBI
16	Li C, Tang Z, Zhang W, Ye Z and Liu F: GEPIA2021: integrating multiple deconvolution-based analysis into GEPIA. Nucleic Acids Res. 49:W242–W246. 2021.PubMed/NCBI
17	Rao X, Huang X, Zhou Z and Lin X: An improvement of the 2ˆ(-delta delta CT) method for quantitative real-time polymerase chain reaction data analysis. Biostat Bioinforma Biomath. 3:71–85. 2013.PubMed/NCBI
18	Shen A, Liu L, Chen H, Qi F, Huang Y, Lin J, Sferra TJ, Sankararaman S, Wei L, Chu J, et al: Cell division cycle associated 5 promotes colorectal cancer progression by activating the ERK signaling pathway. Oncogenesis. 8:192019.PubMed/NCBI
19	Hubrecht RC and Carter E: The 3Rs and humane experimental technique: Implementing change. Animals (Basel). 9:7542019.PubMed/NCBI
20	Calderón-González KG, Valero Rustarazo ML, Labra-Barrios ML, Bazán-Méndez CI, Tavera-Tapia A, Herrera-Aguirre ME, Sánchez del Pino MM, Gallegos-Pérez JL, González-Márquez H, Hernández-Hernández JM, et al: Determination of the protein expression profiles of breast cancer cell lines by quantitative proteomics using iTRAQ labelling and tandem mass spectrometry. J Proteomics. 124:50–78. 2015.PubMed/NCBI
21	Ma YT, Xiao Q, Xu X, Shao and Wang H: iTRAQ-based quantitative analysis of cancer-derived secretory proteome reveals TPM2 as a potential diagnostic biomarker of colorectal cancer. Front Med. 10:278–285. 2016.PubMed/NCBI
22	Kanehisa M and Goto S: KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 28:27–30. 2000.
23	Milacic M, Beavers D, Conley P, Gong C, Gillespie M, Griss J, Haw R, Jassal B, Matthews L, May B, et al: The reactome pathway knowledgebase 2024. Nucleic Acids Res. 52:D672–D678. 2024.
24	Mi H and Thomas P: PANTHER pathway: An ontology-based pathway database coupled with data analysis tools. Methods Mol Biol. 563:123–140. 2009.PubMed/NCBI
25	Li F, Zhao D, Yang S, Wang J, Li Q, Jin X and Wang W: ITRAQ-based proteomics analysis of triptolide on human A549 lung adenocarcinoma cells. Cell Physiol Biochem. 45:917–934. 2018.PubMed/NCBI
26	Kanehisa M, Furumichi M, Tanabe M, Sato Y and Morishima K: KEGG: New perspectives on genomes, pathways, diseases and drugs. Nucleic Acids Res. 45:D353–D361. 2017.
27	Kulak NA, Pichler G, Paron I, Nagaraj N and Mann M: Minimal, encapsulated proteomic-sample processing applied to copy-number estimation in eukaryotic cells. Nat Methods. 11:319–324. 2014.PubMed/NCBI
28	Humphrey SJ, Azimifar SB and Mann M: High-throughput phosphoproteomics reveals in vivo insulin signaling dynamics. Nat Biotechnol. 33:990–995. 2015.PubMed/NCBI
29	Collado M, Blasco MA and Serrano M: Cellular senescence in cancer and aging. Cell. 130:223–233. 2007.PubMed/NCBI
30	Kurz DJ, Decary S, Hong Y and Erusalimsky JD: Senescence-associated (beta)-galactosidase reflects an increase in lysosomal mass during replicative ageing of human endothelial cells. J Cell Sci. 113:3613–3622. 2000.PubMed/NCBI
31	Bannister AJ, Zegerman P, Partridge JF, Miska EA, Thomas JO, Allshire RC and Kouzarides T: Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain. Nature. 410:120–124. 2001. View Article : Google Scholar : PubMed/NCBI
32	Hanahan D and Weinberg RA: Hallmarks of cancer: The next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI
33	Hanahan D and Weinberg RA: The hallmarks of cancer. Cell. 100:57–70. 2000. View Article : Google Scholar : PubMed/NCBI
34	Kramer HB, Lai CF, Patel H, Periyasamy M, Lin ML, Feller SM, Fuller-Pace FV, Meek DW, Ali S and Buluwela L: LRH-1 drives colon cancer cell growth by repressing the expression of the CDKN1A gene in a p53-dependent manner. Nucleic Acids Res. 44:582–594. 2016. View Article : Google Scholar :
35	Wang G, Fu Y, Hu F, Lan J, Xu F, Yang X, Luo X, Wang J and Hu J: Loss of BRG1 induces CRC cell senescence by regulating p53/p21 pathway. Cell Death Dis. 8:e26072017. View Article : Google Scholar : PubMed/NCBI
36	Shen A, Wu M, Liu L, Chen Y, Chen X, Zhuang M, Xie Q, Cheng Y, Li J, Shen Z, et al: Targeting NUFIP1 suppresses growth and induces senescence of colorectal cancer cells. Front Oncol. 11:6814252021. View Article : Google Scholar : PubMed/NCBI
37	Ohtani N, Mann DJ and Hara E: Cellular senescence: Its role in tumor suppression and aging. Cancer Sci. 100:792–797. 2009. View Article : Google Scholar : PubMed/NCBI
38	Shen Y and White V: p53-dependent apoptosis pathways. Adv Cancer Res. 82:55–84. 2001. View Article : Google Scholar : PubMed/NCBI
39	Stein GH, Drullinger LF, Soulard A and Dulić V: Differential roles for cyclin-dependent kinase inhibitors p21 and p16 in the mechanisms of senescence and differentiation in human fibroblasts. Mol Cell Biol. 19:2109–2117. 1999. View Article : Google Scholar : PubMed/NCBI
40	Li XL, Zhou J, Chen ZR and Chng WJ: P53 mutations in colorectal cancer-molecular pathogenesis and pharmacological reactivation. World J Gastroenterol. 21:84–93. 2015. View Article : Google Scholar : PubMed/NCBI