Characteristics and Interactive Regulation of Metabolic Reprogramming and Protein Post-translational Modifications in Oral Squamous Cell Carcinoma

doi:10.13701/j.cnki.kqyxyj.2026.04.001

Abstract

Abstract: Oral squamous cell carcinoma (OSCC), the most prevalent malignant tumor of the head and neck, exhibits high rates of recurrence and metastasis, necessitating novel therapeutic targets. Metabolic reprogramming and post-translational modifications (PTMs), recognized as core hallmarks of cancer, play a critical interactive role in OSCC progression. OSCC demonstrates significant metabolic remodeling features: enhanced glycolysis, dynamic remodeling of the tricarboxylic acid (TCA) cycle and oxidative phosphorylation, dysregulated amino acid metabolism, and hyperactive lipid synthesis, supplying energy and biosynthetic precursors for cancer cells. Metabolic intermediates can serve as substrates or cofactors for PTMs, directly regulating epigenetic reprogramming. Conversely, PTMs dynamically modulate the activity and flux of metabolic enzymes through mechanisms such as phosphorylation and ubiquitination, enabling feedback regulation of metabolic pathways. This bidirectional crosstalk synergistically drives the malignant progression of OSCC. This review summarizes these mechanisms, aiming to provide novel theoretical foundations for molecular subtyping and targeted therapeutic strategies in OSCC.

Key words: oral squamous cell carcinoma, metabolic reprogramming, post-translational modifications, interactive regulation

YIN Xiteng, HAN Wei. Characteristics and Interactive Regulation of Metabolic Reprogramming and Protein Post-translational Modifications in Oral Squamous Cell Carcinoma[J]. Journal of Oral Science Research, 2026, 42(4): 269-273.

References

[1] Tan Y, Wang Z, Xu M, et al. Oral squamous cell carciomas: state of the field and emerging directions [J]. Int J Oral Sci, 2023, 15(1): 44.
[2] Faubert B, Solmonson A, DeBerardinis RJ. Metabolic reprogramming and cancer progression [J]. Science, 2020, 368(6487):eaaw5473.
[3] Li W, Li F, Zhang X, et al. Insights into the post-translational modification and its emerging role in shaping the tumor microenvironment [J]. Signal Transduct Target Ther, 2021, 6(1): 422.
[4] Wang Y, Zhang X, Wang S, et al. Identification of metabolism-associated biomarkers for early and precise diagnosis of oral squamous cell carcinoma [J]. Biomolecules, 2022, 12(3):400.
[5] Huang G, Chen S, Washio J, et al. Glycolysis-related gene analyses indicate that depdc1 promotes the malignant progression of oral squamous cell carcinoma via the WNT/beta-catenin signaling pathway [J]. Int J Mol Sci, 2023, 24(3):1992.
[6] Botha H, Farah CS, Koo K, et al. The role of glucose transporters in oral squamous cell carcinoma [J]. Biomolecules, 2021, 11(8):1070.
[7] Zheng Z, Ma X, Li H. Circular RNA circMDM2 accelerates the glycolysis of oral squamous cell carcinoma by targeting miR-532-3p/HK2 [J]. J Cell Mol Med, 2020, 24(13): 7531-7537.
[8] Zhao C, Zhou Y, Ma H, et al. A four-hypoxia-genes-based prognostic signature for oral squamous cell carcinoma [J]. BMC Oral Health, 2021, 21(1): 232.
[9] Zhang Y, Cai H, Liao Y, et al. Activation of PGK1 under hypoxic conditions promotes glycolysis and increases stem cell-like properties and the epithelial-mesenchymal transition in oral squamous cell carcinoma cells via the AKT signalling pathway [J]. Int J Oncol, 2020, 57(3): 743-755.
[10] Arnold PK, Finley LWS. Regulation and function of the mammalian tricarboxylic acid cycle [J]. J Biol Chem, 2023, 299(2): 102838.
[11] Wang Z, Tang S, Cai L, et al. DRP1 inhibition-mediated mitochondrial elongation abolishes cancer stemness, enhances glutaminolysis, and drives ferroptosis in oral squamous cell carcinoma [J]. Br J Cancer, 2024, 130(11): 1744-1757.
[12] Noh JK, Woo SR, Kong M, et al. Gene signature predicting recurrence in oral squamous cell carcinoma is characterized by increased oxidative phosphorylation [J]. Mol Oncol, 2023, 17(1): 134-149.
[13] Kosaisawe N, Sparta B, Pargett M, et al. Transient phases of OXPHOS inhibitor resistance reveal underlying metabolic heterogeneity in single cells [J]. Cell Metab, 2021, 33(3): 649-665.e8.
[14] Yang R, Zhang S, Wang L, et al. Radiation-induced exosomes promote oral squamous cell carcinoma progression via enhancing SLC1A5-glutamine metabolism [J]. J Oral Pathol Med, 2024, 53(7): 458-467.
[15] Yang J, Chen F, Lang L, et al. Therapeutic targeting of the GLS1-c-Myc positive feedback loop suppresses glutaminolysis and inhibits progression of head and neck cancer [J]. Cancer Res, 2024, 84(19): 3223-3234.
[16] Fang K, Sun M, Leng Z, et al. Targeting IGF1R signaling enhances the sensitivity of cisplatin by inhibiting proline and arginine metabolism in oesophageal squamous cell carcinoma under hypoxia [J]. J Exp Clin Cancer Res, 2023, 42(1): 73.
[17] Yuan Z, Li M, Tang Z. BCAT1 promotes cell proliferation, migration, and invasion via the PI3K-Akt signaling pathway in oral squamous cell carcinoma [J]. Oral Dis, 2025, 31(2): 364-375.
[18] Xu M, Zhu F, Yin Q, et al. Serum response factor-regulated IDO1/Kyn-Ahr pathway promotes tumorigenesis of oral squamous cell carcinoma [J]. Cancers (Basel), 2023, 15(4):1319.
[19] Shao Y, Du Y, Chen Z, et al. Mesenchymal stem cell-mediated adipogenic transformation: a key driver of oral squamous cell carcinoma progression [J]. Stem Cell Res Ther, 2025, 16(1):12.
[20] Schminke B, Shomroni O, Salinas G, et al. Prognostic factor identification by screening changes in differentially expressed genes in oral squamous cell carcinoma [J]. Oral Dis, 2023, 29(1): 116-127.
[21] Chan NN, Yamazaki M, Maruyama S, et al. Cholesterol is a regulator of CAV1 localization and cell migration in oral squamous cell carcinoma [J]. Int J Mol Sci, 2023, 24(7):6035.
[22] Li L, Ji S, Shrestha C, et al. p120-catenin suppresses proliferation and tumor growth of oral squamous cell carcinoma via inhibiting nuclear phospholipase C-gamma1 signaling [J]. J Cell Physiol, 2020, 235(12): 9399-9413.
[23] Zhou Q, Liu S, Kou Y, et al. ATP promotes oral squamous cell carcinoma cell invasion and migration by activating the PI3K/AKT pathway via the P2Y2-Src-EGFR axis [J]. ACS Omega, 2022, 7(44): 39760-39771.
[24] Xu H, Cheng G, Niu Q, et al. Spindle and kinetochore-associated complex 3 promotes cell growth via the PI3K/AKT/GSK3beta and PI3K/AKT/FOXO1 pathways and is a potential prognostic biomarker for oral squamous cell carcinoma [J]. Oral Surg Oral Med Oral Pathol Oral Radiol, 2022, 134(5): 599-614.
[25] Wei LY, Lin HC, Tsai FC, et al. Effects of interleukin-6 on STAT3-regulated signaling in oral cancer and as a prognosticator of patient survival [J]. Oral Oncol, 2022, 124: 105665.
[26] Kaliyaperumal K, Sharma AK, McDonald DG, et al. S-Nitrosoglutathione-mediated STAT3 regulation in efficacy of radiotherapy and cisplatin therapy in head and neck squamous cell carcinoma [J]. Redox Biol, 2015, 6: 41-50.
[27] Koo N, Sharma AK, Narayan S. Therapeutics targeting p53-MDM2 interaction to induce cancer cell death [J]. Int J Mol Sci, 2022, 23(9):5005.
[28] Mohanty S, Mohapatra P, Shriwas O, et al. CRISPR-based kinome-screening revealed MINK1 as a druggable player to rewire 5FU-resistance in OSCC through AKT/MDM2/p53 axis [J]. Oncogene, 2022, 41(45): 4929-4940.
[29] Qiu B, Sun Y, Nie W, et al. FBXW7 promotes autophagy and inhibits proliferation of oral squamous cell carcinoma [J]. Immun Inflamm Dis, 2023, 11(5): e845.
[30] Liu T, Liu J, Chen Q, et al. Expression of USP22 and the chromosomal passenger complex is an indicator of malignant progression in oral squamous cell carcinoma [J]. Oncol Lett, 2019, 17(2): 2040-2046.
[31] Xu C, Xu Q, Yang H. H3K27 acetylation-activated GLDC accelerated the advancement of oral squamous cell carcinoma by suppressing the p53 signaling pathway [J]. Environ Toxicol, 2025, 40(1): 140-151.
[32] Li W, Zhu D, Qin S. SIRT7 suppresses the epithelial-to-mesenchymal transition in oral squamous cell carcinoma metastasis by promoting SMAD4 deacetylation [J]. J Exp Clin Cancer Res, 2018, 37(1): 148.
[33] Yin X, Zhang H, Wei Z, et al. Large-scale identification of lysine crotonylation reveals its potential role in oral squamous cell carcinoma [J]. Cancer Manag Res, 2023, 15: 1165-1179.
[34] Song F, Hou C, Huang Y, et al. Lactylome analyses suggest systematic lysine-lactylated substrates in oral squamous cell carcinoma under normoxia and hypoxia [J]. Cell Signal, 2024, 120: 111228.
[35] Jing F, Zhu L, Zhang J, et al. Multi-omics reveals lactylation-driven regulatory mechanisms promoting tumor progression in oral squamous cell carcinoma [J]. Genome Biol, 2024, 25(1): 272.
[36] Yang Z, Liu F, Li Z, et al. Histone lysine methyltransferase SMYD3 promotes oral squamous cell carcinoma tumorigenesis via H3K4me3-mediated HMGA2 transcription [J]. Clin Epigenetics, 2023, 15(1): 92.
[37] Chiang WF, Cheng TM, Chang CC, et al. Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) promotes EGF receptor signaling of oral squamous cell carcinoma metastasis via the complex N-glycosylation [J]. Oncogene, 2018, 37(1): 116-127.
[38] aval T, Alisson-Silva F, Schwarz F. Roles of glycosylation at the cancer cell surface: opportunities for large scale glycoproteomics [J]. Theranostics, 2023, 13(8): 2605-2615.
[39] Fu C, Yuan G, Yang ST, et al. RGS12 represses oral cancer via the phosphorylation and SUMOylation of PTEN [J]. J Dent Res, 2021, 100(5): 522-531.
[40] Huang J, Yang JG, Ren JG, et al. Overexpression of RAB27A in oral squamous cell carcinoma promotes tumor migration and invasion via modulation of EGFR membrane stability [J]. Int J Mol Sci, 2023, 24(17):13103.
[41] Zhang Z, Xie H, Zuo W, et al. Lysine 2-hydroxyisobutyrylation proteomics reveals protein modification alteration in the actin cytoskeleton pathway of oral squamous cell carcinoma [J]. J Proteomics, 2021, 249: 104371.
[42] Yang R, Zhang G, Meng Z, et al. Glutamate dehydrogenase 1-catalytic glutaminolysis feedback activates EGFR/PI3K/AKT pathway and reprograms glioblastoma metabolism [J]. Neuro Oncol, 2025, 27(3): 668-681.
[43] Liu P, Wang Y, Li X, et al. Enhanced lipid biosynthesis in oral squamous cell carcinoma cancer-associated fibroblasts contributes to tumor progression: Role of IL8/AKT/p-ACLY axis [J]. Cancer Sci, 2024, 115(5): 1433-1445.
[44] Ohashi T, Terazawa K, Shibata H, et al. Metabolic profiling analysis of head and neck squamous cell carcinoma [J]. Oral Dis, 2024, 30(2): 342-352.
[45] Kao YY, Chou CH, Yeh LY, et al. MicroRNA miR-31 targets SIRT3 to disrupt mitochondrial activity and increase oxidative stress in oral carcinoma [J]. Cancer Lett, 2019, 456: 40-48.
[46] Gong X, Tang H, Yang K. PER1 suppresses glycolysis and cell proliferation in oral squamous cell carcinoma via the PER1/RACK1/PI3K signaling complex [J]. Cell Death Dis, 2021, 12(3): 276.
[47] Yang X, Ma H, Zhang M, et al. TRIM32 promotes oral squamous cell carcinoma progression by enhancing FBP2 ubiquitination and degradation [J]. Biochem Biophys Res Commun, 2023, 678: 165-172.
[48] Zhang G, Zhao X, Liu W. NEDD4L inhibits glycolysis and proliferation of cancer cells in oral squamous cell carcinoma by inducing ENO1 ubiquitination and degradation [J]. Cancer Biol Ther, 2022, 23(1): 243-253.