Research progress of GALNT3 as a potential tumor molecular marker and drug target

doi:10.3969/j.issn.1674-8115.2024.11.014

Abstract

Abstract:

Mucin-type O-glycosylation is one of the most common post-translational modifications in proteins, capable of altering protein conformation and biological functions. It plays a crucial role in biological processes such as cell signaling, cell adhesion, and immune responses. Polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3), as the initiating enzyme of mucin-type O-glycosylation, is of paramount importance in maintaining the homeostasis of human cells and tissues. Dysfunction of GALNT3 has been found to play a role in various diseases, such as calcium-phosphorus metabolism disorders and atherosclerosis. Additionally, GALNT3 is abnormally expressed in several types of tumors, including colorectal cancer, lung cancer, and ovarian cancer. Its expression is associated with the clinical pathological features of patients and poor prognosis, making it a potential biomarker for early tumor diagnosis and prognosis evaluation. Further research shows that GALNT3 can both regulate glycosylation levels to reduce adhesion between tumor cells and activate multiple metabolism-related pathways, promoting tumor cell invasion and metastasis. This review summarizes the role of GALNT3 in the development of malignant tumors and discusses the prospects and challenges of developing anti-tumor drugs targeting GALNT3.

Key words: polypeptide N-acetylgalactosaminyltransferase 3, mucin type O-glycosylation, tumor marker, hematologic malignancy

CLC Number:

R730.23

GAO Yixuan, ZHANG Yichi, DAI Luyan, MA Jiao. Research progress of GALNT3 as a potential tumor molecular marker and drug target[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2024, 44(11): 1460-1465.

Figures/Tables 1

TrendMD

References 52

1	VAN DEN STEEN P, RUDD P M, DWEK R A, et al. Concepts and principles of O-linked glycosylation[J]. Crit Rev Biochem Mol Biol, 1998, 33(3): 151-208.
2	ESMAIL S, MANOLSON M F. Advances in understanding N-glycosylation structure, function, and regulation in health and disease[J]. Eur J Cell Biol, 2021, 100(7/8): 151186.
3	WANDALL H H, NIELSEN M A I, KING-SMITH S, et al. Global functions of O-glycosylation: promises and challenges in O-glycobiology[J]. FEBS J, 2021, 288(24): 7183-7212.
4	GARAY Y C, CEJAS R B, LORENZ V, et al. Polypeptide N-acetylgalactosamine transferase 3: a post-translational writer on human health[J]. J Mol Med, 2022, 100(10): 1387-1403.
5	ČAVAL 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.
6	MAGALHÃES A, DUARTE H O, REIS C A. The role of O-glycosylation in human disease[J]. Mol Aspects Med, 2021, 79: 100964.
7	LI S D, QI Y, HUANG Y R, et al. Exosome-derived SNHG16 sponging miR-4500 activates HUVEC angiogenesis by targeting GALNT1 via PI3K/Akt/mTOR pathway in hepatocellular carcinoma[J]. J Physiol Biochem, 2021, 77(4): 667-682.
8	LIU S Y, SHUN C T, HUNG K Y, et al. Mucin glycosylating enzyme GALNT2 suppresses malignancy in gastric adenocarcinoma by reducing MET phosphorylation[J]. Oncotarget, 2016, 7(10): 11251-11262.
9	LIU C, LI Z, XU L, et al. GALNT6 promotes breast cancer metastasis by increasing mucin-type O-glycosylation of α2M[J]. Aging, 2020, 12(12): 11794-11811.
10	PENG X D, CHEN X R, ZHU X T, et al. GALNT6 knockdown inhibits the proliferation and migration of colorectal cancer cells and increases the sensitivity of cancer cells to 5-FU[J]. J Cancer, 2021, 12(24): 7413-7421.
11	LI H W, LIU M B, JIANG X, et al. GALNT14 regulates ferroptosis and apoptosis of ovarian cancer through the EGFR/mTOR pathway[J]. Future Oncol, 2022, 18(2): 149-161.
12	MARIMUTHU S, BATRA S K, PONNUSAMY M P. Pan-cancer analysis of altered glycosyltransferases confers poor clinical outcomes[J]. Clin Transl Discov, 2022, 2(2): e100.
13	MAO C Z, ZHUANG S M, XIA Z J, et al. Pan-cancer analysis of GALNTs expression identifies a prognostic of GALNTs feature in low grade glioma[J]. J Leukoc Biol, 2022, 112(4): 887-899.
14	RODRIGUEZ E, BOELAARS K, BROWN K, et al. Analysis of the glyco-code in pancreatic ductal adenocarcinoma identifies glycan-mediated immune regulatory circuits[J]. Commun Biol, 2022, 5(1): 41.
15	MEIJLINK F, CURRAN T, MILLER A D, et al. Removal of a 67-base-pair sequence in the noncoding region of protooncogene fos converts it to a transforming gene[J]. Proc Natl Acad Sci U S A, 1985, 82(15): 4987-4991.
16	HO B B, BERGWITZ C. FGF23 signalling and physiology[J]. J Mol Endocrinol, 2021, 66(2): R23-R32.
17	HASSAN N, GREGSON C L, TANG H T, et al. Rare and common variants in GALNT3 may affect bone mass independently of phosphate metabolism[J]. J Bone Miner Res, 2023, 38(5): 678-691.
18	ITO N, FUKUMOTO S. Congenital hyperphosphatemic conditions caused by the deficient activity of FGF23[J]. Calcif Tissue Int, 2021, 108(1): 104-115.
19	GUO L W, LI D, LI M T, et al. Variant in GALNT3 gene linked with reduced coronary artery disease risk in Chinese population[J]. DNA Cell Biol, 2017, 36(7): 529-534.
20	WANG Y K, LI S J, ZHOU L L, et al. GALNT3 protects against vascular calcification by reducing oxidative stress and apoptosis of smooth muscle cells[J]. Eur J Pharmacol, 2023, 939: 175447.
21	GUO L W, WANG L Y, LI H F, et al. Down regulation of GALNT3 contributes to endothelial cell injury via activation of p38 MAPK signaling pathway[J]. Atherosclerosis, 2016, 245: 94-100.
22	BENNETT E P, MANDEL U, CLAUSEN H, et al. Control of mucin-type O-glycosylation: a classification of the polypeptide GalNAc-transferase gene family[J]. Glycobiology, 2012, 22(6): 736-756.
23	RAGHU D, MOBLEY R J, SHENDY N A M, et al. GALNT3 maintains the epithelial state in trophoblast stem cells[J]. Cell Rep, 2019, 26(13): 3684-3697.e7.
24	PELUSO G, TIAN E, ABUSLEME L, et al. Loss of the disease-associated glycosyltransferase Galnt3 alters Muc10 glycosylation and the composition of the oral microbiome[J]. J Biol Chem, 2020, 295(5): 1411-1425.
25	NYGAARD M B, HERLIHY A S, JEANNEAU C, et al. Expression of the O-glycosylation enzyme GalNAc-T3 in the equatorial segment correlates with the quality of spermatozoa[J]. Int J Mol Sci, 2018, 19(10): 2949.
26	BAGDONAITE I, PALLESEN E M, YE Z L, et al. O-glycan initiation directs distinct biological pathways and controls epithelial differentiation[J]. EMBO Rep, 2020, 21(6): e48885.
27	ONITSUKA K, SHIBAO K, NAKAYAMA Y, et al. Prognostic significance of UDP-N-acetyl-α-D-galactosamine: polypeptide N-acetylgalactosaminyltransferase-3 (GalNAc-T3) expression in patients with gastric carcinoma[J]. Cancer Sci, 2003, 94(1): 32-36.
28	KITADA S, YAMADA S, KUMA A, et al. Polypeptide N-acetylgalactosaminyl transferase 3 independently predicts high-grade tumours and poor prognosis in patients with renal cell carcinomas[J]. Br J Cancer, 2013, 109(2): 472-481.
29	WANG Z Q, BACHVAROVA M, MORIN C, et al. Role of the polypeptide N-acetylgalactosaminyltransferase 3 in ovarian cancer progression: possible implications in abnormal mucin O-glycosylation[J]. Oncotarget, 2014, 5(2): 544-560.
30	LUO D, FANG M Y, SHAO L, et al. The EMT-related genes GALNT3 and OAS1 are associated with immune cell infiltration and poor prognosis in lung adenocarcinoma[J]. Front Biosci, 2023, 28(10): 271.
31	SHIBAO K, IZUMI H, NAKAYAMA Y, et al. Expression of UDP-N-acetyl-α-D-galactosamine-polypeptide galNAc N-acetylgalactosaminyl transferase-3 in relation to differentiation and prognosis in patients with colorectal carcinoma[J]. Cancer, 2002, 94(7): 1939-1946.
32	MOCHIZUKI Y, ITO K, IZUMI H, et al. Expression of polypeptide N-acetylgalactosaminyl transferase-3 and its association with clinicopathological factors in thyroid carcinomas[J]. Thyroid, 2013, 23(12): 1553-1560.
33	BARKEER S, CHUGH S, KARMAKAR S, et al. Novel role of O-glycosyltransferases GALNT3 and B3GNT3 in the self-renewal of pancreatic cancer stem cells[J]. BMC Cancer, 2018, 18(1): 1157.
34	LIU B, PAN S M, XIAO Y, et al. LINC01296/miR-26a/GALNT3 axis contributes to colorectal cancer progression by regulating O-glycosylated MUC1 via PI3K/AKT pathway[J]. J Exp Clin Cancer Res, 2018, 37(1): 316.
35	SUN L X, SUN W, SONG H B, et al. MiR-885-5p inhibits proliferation and metastasis by targeting IGF2BP1 and GALNT3 in human intrahepatic cholangiocarcinoma[J]. Mol Carcinog, 2020, 59(12): 1371-1381.
36	ISHIKAWA M, KITAYAMA J, NARIKO H, et al. The expression pattern of UDP-N-acetyl-α-D-galactosamine: polypeptide N-acetylgalactosaminyl transferase-3 in early gastric carcinoma[J]. J Surg Oncol, 2004, 86(1): 28-33.
37	PARK M S, YANG A Y, LEE J E, et al. GALNT3 suppresses lung cancer by inhibiting myeloid-derived suppressor cell infiltration and angiogenesis in a TNFR and c-MET pathway-dependent manner[J]. Cancer Lett, 2021, 521: 294-307.
38	PANG X C, LI H J, GUAN F, et al. Multiple roles of glycans in hematological malignancies[J]. Front Oncol, 2018, 8: 364.
39	OLIVEIRA T, ZHANG M F, JOO E J, et al. Glycoproteome remodeling in MLL-rearranged B-cell precursor acute lymphoblastic leukemia[J]. Theranostics, 2021, 11(19): 9519-9537.
40	SUPRUNIUK K, RADZIEJEWSKA I. MUC1 is an oncoprotein with a significant role in apoptosis (Review)[J]. Int J Oncol, 2021, 59(3): 68.
41	ALOBAIDI N K, ALWAN A F, AL-REKABI A N. Assessment of LAG3 and GALNT11 gene expression in patients with chronic lymphocytic leukemia and their impact on disease progression[J]. Biochem Cell Arch, 2021, 21(1): 809-818.
42	PATSOS G, HEBBE-VITON V, ROBBE-MASSELOT C, et al. O-glycan inhibitors generate aryl-glycans, induce apoptosis and lead to growth inhibition in colorectal cancer cell lines[J]. Glycobiology, 2009, 19(4): 382-398.
43	SONG L N, LINSTEDT A D. Inhibitor of ppGalNAc-T3-mediated O-glycosylation blocks cancer cell invasiveness and lowers FGF23 levels[J]. eLife, 2017, 6: e24051.
44	KIM Y K. RNA therapy: current status and future potential[J]. Chonnam Med J, 2020, 56(2): 87-93.
45	CHENG D, CHU F F, LIANG F, et al. Downregulation of circ-RAPGEF5 inhibits colorectal cancer progression by reducing the expression of polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3)[J]. Environ Toxicol, 2024, 39(8): 4249-4260.
46	ZHANG X Y, XIE K, ZHOU H H, et al. Role of non-coding RNAs and RNA modifiers in cancer therapy resistance[J]. Mol Cancer, 2020, 19(1): 47.
47	TAHERIAZAM A, BAYANZADEH S D, HEYDARI FARAHANI M, et al. Non-coding RNA-based therapeutics in cancer therapy: an emphasis on Wnt/β-catenin control[J]. Eur J Pharmacol, 2023, 951: 175781.
48	ROBINSON E L, PORT J D. Utilization and potential of RNA-based therapies in cardiovascular disease[J]. JACC Basic Transl Sci, 2022, 7(9): 956-969.
49	PAUNOVSKA K, LOUGHREY D, DAHLMAN J E. Drug delivery systems for RNA therapeutics[J]. Nat Rev Genet, 2022, 23(5): 265-280.
50	PARK H, OTTE A, PARK K. Evolution of drug delivery systems: from 1950 to 2020 and beyond[J]. J Control Release, 2022, 342: 53-65.
51	KHAN M I, HOSSAIN M I, HOSSAIN M K, et al. Recent progress in nanostructured smart drug delivery systems for cancer therapy: a review[J]. ACS Appl Bio Mater, 2022, 5(3): 971-1012.
52	NARIMATSU Y, JOSHI H J, YANG Z, et al. A validated gRNA library for CRISPR/Cas9 targeting of the human glycosyltransferase genome[J]. Glycobiology, 2018, 28(5): 295-305.

[1]	WANG Mengfei, YANG Shouzhi, QIAO Yongxia, HUANG Lin. Establishment of discriminative models for predicting the infiltration degree of patients with lung adenocarcinoma based on clinical laboratory indicators [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2024, 44(1): 98-107.
[2]	LIU Jin-yan, ZHAO Jun-tao, WANG Heng-ru, HUANG Jia-yi, WANG Yu-ting, XIANG Ming-jie. Effect of cytoskeleton-associated protein 4 on tumor diagnosis and prognosis [J]. , 2020, 40(2): 255-.
[3]	ZHENG Tian-yu, DU Jun, CHEN Ning, NI Pei-hua, XUE Hui-ping. Roles of exosomes in tumor diagnosis and treatment#br# [J]. , 2017, 37(7): 1046-.
[4]	XU Yuan-yuan, ZHAO Hong, ZHANG Yu, SUN Jiao, GU Qin, WANG Hai-dong, ZHU Jun-qiu. Analysis of levels of five serum tumor markers and related influencing factors for elderly patients with type 2 diabetes [J]. , 2016, 36(7): 1044-.
[5]	GU Wen-li, WU Jing-jing. Expression of circulating miR-4677 of patients with oral squamous cell carcinoma [J]. , 2015, 35(3): 348-.
[6]	JIANG Yi-mei, ZHAO Ren. Predictive values of tumor markers in colorectal cancer [J]. , 2015, 35(11): 1734-.
[7]	HUA Zi-chen, ZHU Zheng-lun, ZHU Zheng-gang. Application of serum tumor markers for diagnosis and treatment of gastric cancer [J]. , 2014, 34(9): 1411-.
[8]	ZHAO Shi-yan, NIE Xiu-li, LIU Xing-dang, et al. Application and advances of detection technology for tumor markers [J]. , 2011, 31(11): 1647-.