Role of UGT in metabolism of malignant tumors and clinical significance

doi:10.3760/cma.j.cn371439-20250704-00026

Abstract

Abstract:

Uridine diphosphate-glucuronosyltransferases （UGTs） are key rate-limiting phase Ⅱ enzymes that mediate the glucuronidation of endobiotics and xenobiotics，thereby governing the clearance and signal transduction. UGTs drive oncogenesis，progression and chemoresistance in breast cancer，lung cancer，prostate cancer，and chronic lymphocytic leukemia by regulating estrogen/androgen levels and related receptors，as well as glycolytic and associated signaling pathways. Further exploration of the dual roles of UGTs in various cancer metabolism and the clinical significance will provide novel biomarkers and therapeutic targets for tumor diagnosis，prognosis assessment and precise medication.

Key words: Neoplasms, Uridine diphosphate glucuronic acid, Metabolic detoxication，phase Ⅱ

Qiao Jinyang, Li Hui, Feng Qinmei. Role of UGT in metabolism of malignant tumors and clinical significance[J]. Journal of International Oncology, 2026, 53(3): 163-166.

References 36

[1]	Hu DG, Marri S, Mackenzie PI, et al. The expression profiles and deregulation of UDP-glycosyltransferase (UGT) genes in human cancers and their association with clinical outcomes[J]. Cancers (Basel), 2021, 13(17): 4491. DOI: 10.3390/cancers13174491.
[2]	Allain EP, Rouleau M, Lévesque E, et al. Emerging roles for UDP-glucuronosyltransferases in drug resistance and cancer progression[J]. Br J Cancer, 2020, 122(9): 1277-1287. DOI: 10.1038/s41416-019-0722-0.
[3]	Zhang L, Ramesh P, Atencia Taboada L, et al. UGT8 mediated sulfatide synthesis modulates BAX localization and dictates apoptosis sensitivity of colorectal cancer[J]. Cell Death Differ, 2025, 32(4): 657-671. DOI: 10.1038/s41418-024-01418-y.
[4]	Ji J, Xie M, Qian Q, et al. SOX9-mediated UGT8 expression promotes glycolysis and maintains the malignancy of non-small cell lung cancer[J]. Biochem Biophys Res Commun, 2022, 587: 139-145. DOI: 10.1016/j.bbrc.2021.11.099.
[5]	Cao Q, Chen X, Wu X, et al. Inhibition of UGT8 suppresses basal-like breast cancer progression by attenuating sulfatide-α_νβ₅ axis[J]. J Exp Med, 2018, 215(6): 1679-1692. DOI: 10.1084/jem.20172048.
[6]	Liu W, Li J, Zhao R, et al. The uridine diphosphate (UDP)-glycosyltransferases (UGTs) superfamily: the role in tumor cell metabolism[J]. Front Oncol, 2022, 12: 1088458. DOI: 10.3389/fonc.2022.1088458.
[7]	Wang SM, Pfeiffer RM, Gierach GL, et al. Use of postmenopausal hormone therapies and risk of histology- and hormone receptor-defined breast cancer: results from a 15-year prospective analysis of NIH-AARP cohort[J]. Breast Cancer Res, 2020, 22(1): 129. DOI: 10.1186/s13058-020-01365-9.
[8]	张喆, 蔡卫民. UGT1A1基因多态性对药物代谢和临床作用影响的进展[J]. 药学实践杂志, 2018, 36(6): 488-492. DOI: 10.3969/j.issn.1006-0111.2018.06.003.
[9]	Li Y, Zhou Y, Mao F, et al. miR-452 reverses abnormal glycosy-lation modification of ERα and estrogen resistance in TNBC (triple-negative breast cancer) through targeting UGT1A1[J]. Front Oncol, 2020, 10: 1509. DOI: 10.3389/fonc.2020.01509.
[10]	Clusan L, Ferrière F, Flouriot G, et al. A basic review on estrogen receptor signaling pathways in breast cancer[J]. Int J Mol Sci, 2023, 24(7): 6834. DOI: 10.3390/ijms24076834.
[11]	Patel R, Klein P, Tiersten A, et al. An emerging generation of endocrine therapies in breast cancer: a clinical perspective[J]. NPJ Breast Cancer, 2023, 9(1): 20. DOI: 10.1038/s41523-023-00523-4. pmid: 37019913
[12]	贺嘉慧, 胡钦勇. 基于GBD数据的中国和美国肺癌发病和死亡趋势及危险因素对比分析[J]. 国际肿瘤学杂志, 2024, 51(1): 29-36. DOI: 10.3760/cma.j.cn371439-20230810-00003.
[13]	金美华, 唐娟, 秦家丽, 等. 2002—2020年间的肺癌流行病学分析[J]. 华夏医学, 2021, 34(6): 34-38. DOI: 10.19296/j.cnki.1008-2409.2021-06-009.
[14]	Hu DG, Marri S, Hulin JA, et al. The somatic mutation landscape of UDP-glycosyltransferase (UGT) genes in human cancers[J]. Cancers (Basel), 2022, 14(22): 5708. DOI: 10.3390/cancers14225708.
[15]	Khan AB, Patel R, McDonald MF, et al. Integrated clinical genomic analysis reveals xenobiotic metabolic genes are downregulated in meningiomas of current smokers[J]. J Neurooncol, 2023, 163(2): 397-405. DOI: 10.1007/s11060-023-04359-7.
[16]	Cong B, Thakur T, Uribe AH, et al. Colon cancer cells evade drug action by enhancing drug metabolism[J]. Oncogene, 2025, 44(36): 3284-3296. DOI: 10.1038/s41388-025-03472-3. pmid: 40634495
[17]	Zhang L, Huang M, Blair IA, et al. Interception of benzo[a]pyrene-7,8-dione by UDP glucuronosyltransferases (UGTs) in human lung cells[J]. Chem Res Toxicol, 2013, 26(10): 1570-1578. DOI: 10.1021/tx400268q. pmid: 24047243
[18]	Rugo HS, Tolaney SM, Loirat D, et al. Safety analyses from the phase 3 ASCENT trial of sacituzumab govitecan in metastatic triple-negative breast cancer[J]. NPJ Breast Cancer, 2022, 8(1): 98. DOI: 10.1038/s41523-022-00467-1. pmid: 36038616
[19]	Lévesque E, Labriet A, Hovington H, et al. Alternative promoters control UGT2B17-dependent androgen catabolism in prostate cancer and its influence on progression[J]. Br J Cancer, 2020, 122(7): 1068-1076. DOI: 10.1038/s41416-020-0749-2.
[20]	Yu L, Li RW, Huang H, et al. Transcriptomic analysis of LNCaP tumor xenograft to elucidate the components and mechanisms contributed by tumor environment as targets for dietary prostate cancer prevention studies[J]. Nutrients, 2021, 13(3): 1000. DOI: 10.3390/nu13031000.
[21]	Cruz-Topete D, Dominic P, Stokes KY. Uncovering sex-specific mechanisms of action of testosterone and redox balance[J]. Redox Biol, 2020, 31: 101490. DOI: 10.1016/j.redox.2020.101490.
[22]	Kaipainen A, Zhang A, Gil da Costa RM, et al. Testosterone accumulation in prostate cancer cells is enhanced by facilitated diffusion[J]. Prostate, 2019, 79(13): 1530-1542. DOI: 10.1002/pros.23874. pmid: 31376206
[23]	Mao Y, Yang G, Li Y, et al. Advances in the current understanding of the mechanisms governing the acquisition of castration-resistant prostate cancer[J]. Cancers (Basel), 2022, 14(15): 3744. DOI: 10.3390/cancers14153744.
[24]	Pisano C, Tucci M, Di Stefano RF, et al. Interactions between androgen receptor signaling and other molecular pathways in prostate cancer progression: current and future clinical implications[J]. Crit Rev Oncol Hematol, 2021, 157: 103185. DOI: 10.1016/j.critrevonc.2020.103185.
[25]	Allain EP, Rouleau M, Vanura K, et al. UGT2B17 modifies drug response in chronic lymphocytic leukaemia[J]. Br J Cancer, 2020, 123(2): 240-251. DOI: 10.1038/s41416-020-0887-6.
[26]	Papamichos SI, Jungbauer C. Comment on: "UGT2B17 modifies drug response in chronic lymphocytic leukaemia"[J]. Br J Cancer, 2020, 123(8): 1345-1346. DOI: 10.1038/s41416-020-1005-5.
[27]	Chen Y, Chen L, Yu J, et al. Cirmtuzumab blocks Wnt5a/ROR1 stimulation of NF-κB to repress autocrine STAT3 activation in chronic lymphocytic leukemia[J]. Blood, 2019, 134(13): 1084-1094. DOI: 10.1182/blood.2019001366. pmid: 31409670
[28]	Chen Y, Shao X, Yang H, et al. Interferon gamma regulates a complex pro-survival signal network in chronic lymphocytic leukemia[J]. Eur J Haematol, 2023, 110(4): 435-443. DOI: 10.1111/ejh.13921.
[29]	Shao X, Meng X, Yang H, et al. IFN-γ enhances CLL cell resistance to ABT-199 by regulating MCL-1 and BCL-2 expression via the JAK-STAT3 signaling pathway[J]. Leuk Lymphoma, 2023, 64(1): 71-78. DOI: 10.1080/10428194.2022.213140.
[30]	Rouleau M, Villeneuve L, Allain EP, et al. Non-canonical transcriptional regulation of the poor prognostic factor UGT2B17 in chronic lymphocytic leukemic and normal B cells[J]. BMC Cancer, 2024, 24(1): 410. DOI: 10.1186/s12885-024-12143-7. pmid: 38566115
[31]	Allain EP, Rouleau M, Le T, et al. Inactivation of prostaglandin E₂ as a mechanism for UGT2B17-mediated adverse effects in chronic lymphocytic leukemia[J]. Front Oncol, 2019, 9: 606. DOI: 10.3389/fonc.2019.00606. pmid: 31334126
[32]	Holme JA, Vondráček J, Machala M, et al. Lung cancer associated with combustion particles and fine particulate matter (PM_2.5)-the roles of polycyclic aromatic hydrocarbons (PAHs) and the aryl hydrocarbon receptor (AhR)[J]. Biochem Pharmacol, 2023, 216: 115801. DOI: 10.1016/j.bcp.2023.115801.
[33]	Tian M, Xia P, Gou X, et al. CRISPR screen identified that UGT1A9 was required for bisphenols-induced mitochondria dyshomeostasis[J]. Environ Res, 2022, 205: 112427. DOI: 10.1016/j.envres.2021.112427.
[34]	Hulshof EC, de With M, de Man FM, et al. UGT1A1 genotype-guided dosing of irinotecan: a prospective safety and cost analysis in poor metaboliser patients[J]. Eur J Cancer, 2022, 162: 148-157. DOI: 10.1016/j.ejca.2021.12.009. pmid: 34998046
[35]	Sharma NK, Bahot A, Sekar G, et al. Understanding cancer's defense against topoisomerase-active drugs: a comprehensive review[J]. Cancers (Basel), 2024, 16(4): 680. DOI: 10.3390/cancers16040680.
[36]	Milano G, Innocenti F, Minami H. Liposomal irinotecan (Onivyde): exemplifying the benefits of nanotherapeutic drugs[J]. Cancer Sci, 2022, 113(7): 2224-2231. DOI: 10.1111/cas.15377.