Comparison of the serum level of glycine N-methyl transferase (GNMT) enzyme in prostate cancer, benign prostatic hyperplasi and healthy subjects
-
Elham Esmaili
,
Fateme Khalaj
,
Hamid Shafee
,
Mohammad Ranaee
,
Sohhrab Halalkhor
,
Sadra Samavarchi Tehrani
Abstract
Objectives: Prostate cancer (PCa) is regarded as the most common malignancy in men, and it is associated with higher levels of prostate-specific antigen (PSA). Recently, it has been demonstrated that Glycine N-methyltransferase (GNMT) plays a critical role in sarcosine production. There is evidence that the serum levels of this enzyme changes in many malignancies, such as hepatocellular carcinoma, colorectal, and gastric cancer. In the current study, we evaluate the serum levels of GNMT in the PCa, benign prostatic hyperplasia (BPH) and healthy subjects.
Methods: Serum samples were obtained from 85 adult males (29 patients with PCa, 28 patients with BPH and 28 healthy participants) referred to the Shahid Beheshti Hospital in Babol and Shahid Hasheminejad Hospital in Tehran.
Results: Our finding showed that PSA level was significantly higher in PCa group than BPH patients and healthy individuals. Moreover, PCa patients had higher level of GNMT as compared to the BPH patients and healthy controls, but it has not appeared significant. Serum level of GNMT enzyme was positively correlated with age in PCa group. In BPH group, the levels of GNMT was significantly correlated with PSA concentrations.
Conclusion: It seems that serum GNMT level is increased in PC patients. However, more research with a bigger sample size is needed to validate these findings.
1. Yousefi T, Mir SM, Asadi J, Tourani M, Karimian A, Maniati M, et al. In silico analysis of non-synonymous single nucleotide polymorphism in a human KLK-2 gene associated with prostate cancer. Meta Gene. 2019;21:100578. https://doi.org/10.1016/j.mgene.2019.100578
2. Chinigo G, Ruffinatti FA, Munaron L. The potential of TRP channels as new prognostic and therapeutic targets against prostate cancer progression. Biochim Biophys Acta Rev Cancer. 2024;1879(6):189226. https://doi.org/10.1016/j.bbcan.2024.189226
3. Huang YC, Lee CM, Chen M, Chung MY, Chang YH, Huang WJ, et al. Haplotypes, loss of heterozygosity, and expression levels of glycine N-methyltransferase in prostate cancer. Clin Cancer Res. 2007;13(5):1412-20. https://doi.org/10.1158/1078-0432.CCR-06-1551
4. Adhyam M, Gupta AK. A Review on the Clinical Utility of PSA in Cancer Prostate. Indian J Surg Oncol. 2012;3(2):120-9. https://doi.org/10.1007/s13193-012-0142-6
5. Junejo NN, AlKhateeb SS. BRCA2 gene mutation and prostate cancer risk. Comprehensive review and update. Saudi Med J. 2020;41(1):9-17. https://doi.org/10.15537/smj.2020.1.24759
6. Kumar S, Gurshaney S, Adagunodo Y, Gage E, Qadri S, Sharma M, et al. Hsp70 and gama-Semino protein as possible prognostic marker of prostate cancer. Front Biosci (Landmark Ed). 2018;23(11):1987-2000. https://doi.org/10.2741/4684
7. Sreekumar A, Poisson LM, Rajendiran TM, Khan AP, Cao Q, Yu J, et al. Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature. 2009;457(7231):910-4. https://doi.org/10.1038/nature07762
8. Yeo EJ, Wagner C. Tissue distribution of glycine N-methyltransferase, a major folate-binding protein of liver. Proc Natl Acad Sci U S A. 1994;91(1):210-4. https://doi.org/10.1073/pnas.91.1.210
9. Yen CH, Hung JH, Ueng YF, Liu SP, Chen SY, Liu HH, et al. Glycine N-methyltransferase affects the metabolism of aflatoxin B1 and blocks its carcinogenic effect. Toxicol Appl Pharmacol. 2009;235(3):296-304. https://doi.org/10.1016/j.taap.2008.12.013
10. Ottaviani S, Brooke GN, O'Hanlon-Brown C, Waxman J, Ali S, Buluwela L. Characterisation of the androgen regulation of glycine N-methyltransferase in prostate cancer cells. J Mol Endocrinol. 2013;51(3):301-12. https://doi.org/10.1530/JME-13-0169
11. Heinzman Z, Schmidt C, Sliwinski MK, Goonesekere NCW. The Case for GNMT as a Biomarker and a Therapeutic Target in Pancreatic Cancer. Pharmaceuticals (Basel). 2021;14(3). https://doi.org/10.3390/ph14030209
12. Oh S, Jo S, Kim HS, Mai VH, Endaya B, Neuzil J, et al. Chemical Biopsy for GNMT as Noninvasive and Tumorigenesis-Relevant Diagnosis of Liver Cancer. Anal Chem. 2023;95(2):1184-92. https://doi.org/10.1021/acs.analchem.2c03944
13. Liu HH, Chen KH, Shih YP, Lui WY, Wong FH, Chen YM. Characterization of reduced expression of glycine N-methyltransferase in cancerous hepatic tissues using two newly developed monoclonal antibodies. J Biomed Sci. 2003;10(1):87-97. https://doi.org/10.1007/BF02256001
14. Senapati D, Sahoo SK, Nayak BS, Senapati S, Kundu GC, Bhattamisra SK. Targeting and engineering biomarkers for prostate cancer therapy. Mol Aspects Med. 2025;103:101359. https://doi.org/10.1016/j.mam.2025.101359
15. Van Poppel H, Albreht T, Basu P, Hogenhout R, Collen S, Roobol M. Serum PSA-based early detection of prostate cancer in Europe and globally: past, present and future. Nat Rev Urol. 2022;19(9):562-72. https://doi.org/10.1038/s41585-022-00638-6
16. Duffy MJ. Biomarkers for prostate cancer: prostate-specific antigen and beyond. Clin Chem Lab Med. 2020;58(3):326-39. https://doi.org/10.1515/cclm-2019-0693
17. Nevo A, Navaratnam A, Andrews P. Prostate cancer and the role of biomarkers. Abdom Radiol (NY). 2020;45(7):2120-32. https://doi.org/10.1007/s00261-019-02305-8
18. Tkac J, Gajdosova V, Hroncekova S, Bertok T, Hires M, Jane E, et al. Prostate-specific antigen glycoprofiling as diagnostic and prognostic biomarker of prostate cancer. Interface Focus. 2019;9(2):20180077. https://doi.org/10.1098/rsfs.2018.0077
19. Haldrup C, Pedersen AL, Ogaard N, Strand SH, Hoyer S, Borre M, et al. Biomarker potential of ST6GALNAC3 and ZNF660 promoter hypermethylation in prostate cancer tissue and liquid biopsies. Mol Oncol. 2018;12(4):545-60. https://doi.org/10.1002/1878-0261.12183
20. Ravi P, Wang V, Fichorova RN, McGregor B, Wei XX, Basaria S, et al. IGF-1 axis changes with ADT and docetaxel in metastatic prostate cancer. Endocr Relat Cancer. 2023;30(11). https://doi.org/10.1530/ERC-23-0241
21. Kerr SJ, Heady JE. Modulation of tRNA methyltransferase activity by competing enzyme systems. Adv Enzyme Regul. 1974;12:103-17. https://doi.org/10.1016/0065-2571(74)90009-0
22. Johnson AA, Cuellar TL. Glycine and aging: Evidence and mechanisms. Ageing Res Rev. 2023;87:101922. https://doi.org/10.1016/j.arr.2023.101922
23. Kishi S, Mori S, Fujiwara-Tani R, Ogata R, Sasaki R, Ikemoto A, et al. ERVK13-1/miR-873-5p/GNMT Axis Promotes Metastatic Potential in Human Bladder Cancer though Sarcosine Production. Int J Mol Sci. 2023;24(22). https://doi.org/10.3390/ijms242216367
24. Moylan CA, Pang H, Dellinger A, Suzuki A, Garrett ME, Guy CD, et al. Hepatic gene expression profiles differentiate presymptomatic patients with mild versus severe nonalcoholic fatty liver disease. Hepatology. 2014;59(2):471-82. https://doi.org/10.1002/hep.26661
25. Fernandez-Alvarez S, Gutierrez-de Juan V, Zubiete-Franco I, Barbier-Torres L, Lahoz A, Pares A, et al. TRAIL-producing NK cells contribute to liver injury and related fibrogenesis in the context of GNMT deficiency. Lab Invest. 2015;95(2):223-36. https://doi.org/10.1038/labinvest.2014.151
26. Fernandez-Tussy P, Fernandez-Ramos D, Lopitz-Otsoa F, Simon J, Barbier-Torres L, Gomez-Santos B, et al. miR-873-5p targets mitochondrial GNMT-Complex II interface contributing to non-alcoholic fatty liver disease. Mol Metab. 2019;29:40-54. https://doi.org/10.1016/j.molmet.2019.08.008
27. Song YH, Shiota M, Kuroiwa K, Naito S, Oda Y. The important role of glycine N-methyltransferase in the carcinogenesis and progression of prostate cancer. Mod Pathol. 2011;24(9):1272-80. https://doi.org/10.1038/modpathol.2011.76
28. Miao L, Liu Y, Chen W, Gao C, Zhang Y, Wei J, et al. Brucine Suppresses Malignant Progression of Prostate Cancer by Decreasing Sarcosine Accumulation via Downregulation of GNMT in the Glycine/sarcosine Metabolic Pathway. Cell Biochem Biophys. 2024;82(3):2373-85. https://doi.org/10.1007/s12013-024-01348-z
29. Zabala-Letona A, Arruabarrena-Aristorena A, Fernandez-Ruiz S, Viera C, Carlevaris O, Ercilla A, et al. PI3K-regulated Glycine N-methyltransferase is required for the development of prostate cancer. Oncogenesis. 2022;11(1):10. https://doi.org/10.1038/s41389-022-00382-x
30. Bianchi F, Dugheri S, Musci M, Bonacchi A, Salvadori E, Arcangeli G, et al. Fully automated solid-phase microextraction-fast gas chromatography-mass spectrometry method using a new ionic liquid column for high-throughput analysis of sarcosine and N-ethylglycine in human urine and urinary sediments. Anal Chim Acta. 2011;707(1-2):197-203. https://doi.org/10.1016/j.aca.2011.09.015
31. Yamkamon V, Yee PP, Yainoi S, Eiamphungporn W, Suksrichavalit T. Simultaneous determination of sarcosine and its related metabolites by gas chromatography-tandem mass spectrometry for prostate cancer diagnosis. EXCLI J. 2018;17:965-79. https://doi.org/10.17179/excli2018-1352
32. Passornraprasit N, Hinestroza JP, Rodthongkum N, Potiyaraj P. Cellulose nanofibers/polyacrylic acid hydrogels integrated with a 3D printed strip: A platform for screening prostate cancer via sarcosine detection. Carbohydr Polym. 2025;352:123134. https://doi.org/10.1016/j.carbpol.2024.123134
33. Markin PA, Brito A, Moskaleva N, Fodor M, Lartsova EV, Shpot YV, et al. Plasma Sarcosine Measured by Gas Chromatography-Mass Spectrometry Distinguishes Prostatic Intraepithelial Neoplasia and Prostate Cancer from Benign Prostate Hyperplasia. Lab Med. 2020;51(6):566-73. https://doi.org/10.1093/labmed/lmaa008
2. Chinigo G, Ruffinatti FA, Munaron L. The potential of TRP channels as new prognostic and therapeutic targets against prostate cancer progression. Biochim Biophys Acta Rev Cancer. 2024;1879(6):189226. https://doi.org/10.1016/j.bbcan.2024.189226
3. Huang YC, Lee CM, Chen M, Chung MY, Chang YH, Huang WJ, et al. Haplotypes, loss of heterozygosity, and expression levels of glycine N-methyltransferase in prostate cancer. Clin Cancer Res. 2007;13(5):1412-20. https://doi.org/10.1158/1078-0432.CCR-06-1551
4. Adhyam M, Gupta AK. A Review on the Clinical Utility of PSA in Cancer Prostate. Indian J Surg Oncol. 2012;3(2):120-9. https://doi.org/10.1007/s13193-012-0142-6
5. Junejo NN, AlKhateeb SS. BRCA2 gene mutation and prostate cancer risk. Comprehensive review and update. Saudi Med J. 2020;41(1):9-17. https://doi.org/10.15537/smj.2020.1.24759
6. Kumar S, Gurshaney S, Adagunodo Y, Gage E, Qadri S, Sharma M, et al. Hsp70 and gama-Semino protein as possible prognostic marker of prostate cancer. Front Biosci (Landmark Ed). 2018;23(11):1987-2000. https://doi.org/10.2741/4684
7. Sreekumar A, Poisson LM, Rajendiran TM, Khan AP, Cao Q, Yu J, et al. Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature. 2009;457(7231):910-4. https://doi.org/10.1038/nature07762
8. Yeo EJ, Wagner C. Tissue distribution of glycine N-methyltransferase, a major folate-binding protein of liver. Proc Natl Acad Sci U S A. 1994;91(1):210-4. https://doi.org/10.1073/pnas.91.1.210
9. Yen CH, Hung JH, Ueng YF, Liu SP, Chen SY, Liu HH, et al. Glycine N-methyltransferase affects the metabolism of aflatoxin B1 and blocks its carcinogenic effect. Toxicol Appl Pharmacol. 2009;235(3):296-304. https://doi.org/10.1016/j.taap.2008.12.013
10. Ottaviani S, Brooke GN, O'Hanlon-Brown C, Waxman J, Ali S, Buluwela L. Characterisation of the androgen regulation of glycine N-methyltransferase in prostate cancer cells. J Mol Endocrinol. 2013;51(3):301-12. https://doi.org/10.1530/JME-13-0169
11. Heinzman Z, Schmidt C, Sliwinski MK, Goonesekere NCW. The Case for GNMT as a Biomarker and a Therapeutic Target in Pancreatic Cancer. Pharmaceuticals (Basel). 2021;14(3). https://doi.org/10.3390/ph14030209
12. Oh S, Jo S, Kim HS, Mai VH, Endaya B, Neuzil J, et al. Chemical Biopsy for GNMT as Noninvasive and Tumorigenesis-Relevant Diagnosis of Liver Cancer. Anal Chem. 2023;95(2):1184-92. https://doi.org/10.1021/acs.analchem.2c03944
13. Liu HH, Chen KH, Shih YP, Lui WY, Wong FH, Chen YM. Characterization of reduced expression of glycine N-methyltransferase in cancerous hepatic tissues using two newly developed monoclonal antibodies. J Biomed Sci. 2003;10(1):87-97. https://doi.org/10.1007/BF02256001
14. Senapati D, Sahoo SK, Nayak BS, Senapati S, Kundu GC, Bhattamisra SK. Targeting and engineering biomarkers for prostate cancer therapy. Mol Aspects Med. 2025;103:101359. https://doi.org/10.1016/j.mam.2025.101359
15. Van Poppel H, Albreht T, Basu P, Hogenhout R, Collen S, Roobol M. Serum PSA-based early detection of prostate cancer in Europe and globally: past, present and future. Nat Rev Urol. 2022;19(9):562-72. https://doi.org/10.1038/s41585-022-00638-6
16. Duffy MJ. Biomarkers for prostate cancer: prostate-specific antigen and beyond. Clin Chem Lab Med. 2020;58(3):326-39. https://doi.org/10.1515/cclm-2019-0693
17. Nevo A, Navaratnam A, Andrews P. Prostate cancer and the role of biomarkers. Abdom Radiol (NY). 2020;45(7):2120-32. https://doi.org/10.1007/s00261-019-02305-8
18. Tkac J, Gajdosova V, Hroncekova S, Bertok T, Hires M, Jane E, et al. Prostate-specific antigen glycoprofiling as diagnostic and prognostic biomarker of prostate cancer. Interface Focus. 2019;9(2):20180077. https://doi.org/10.1098/rsfs.2018.0077
19. Haldrup C, Pedersen AL, Ogaard N, Strand SH, Hoyer S, Borre M, et al. Biomarker potential of ST6GALNAC3 and ZNF660 promoter hypermethylation in prostate cancer tissue and liquid biopsies. Mol Oncol. 2018;12(4):545-60. https://doi.org/10.1002/1878-0261.12183
20. Ravi P, Wang V, Fichorova RN, McGregor B, Wei XX, Basaria S, et al. IGF-1 axis changes with ADT and docetaxel in metastatic prostate cancer. Endocr Relat Cancer. 2023;30(11). https://doi.org/10.1530/ERC-23-0241
21. Kerr SJ, Heady JE. Modulation of tRNA methyltransferase activity by competing enzyme systems. Adv Enzyme Regul. 1974;12:103-17. https://doi.org/10.1016/0065-2571(74)90009-0
22. Johnson AA, Cuellar TL. Glycine and aging: Evidence and mechanisms. Ageing Res Rev. 2023;87:101922. https://doi.org/10.1016/j.arr.2023.101922
23. Kishi S, Mori S, Fujiwara-Tani R, Ogata R, Sasaki R, Ikemoto A, et al. ERVK13-1/miR-873-5p/GNMT Axis Promotes Metastatic Potential in Human Bladder Cancer though Sarcosine Production. Int J Mol Sci. 2023;24(22). https://doi.org/10.3390/ijms242216367
24. Moylan CA, Pang H, Dellinger A, Suzuki A, Garrett ME, Guy CD, et al. Hepatic gene expression profiles differentiate presymptomatic patients with mild versus severe nonalcoholic fatty liver disease. Hepatology. 2014;59(2):471-82. https://doi.org/10.1002/hep.26661
25. Fernandez-Alvarez S, Gutierrez-de Juan V, Zubiete-Franco I, Barbier-Torres L, Lahoz A, Pares A, et al. TRAIL-producing NK cells contribute to liver injury and related fibrogenesis in the context of GNMT deficiency. Lab Invest. 2015;95(2):223-36. https://doi.org/10.1038/labinvest.2014.151
26. Fernandez-Tussy P, Fernandez-Ramos D, Lopitz-Otsoa F, Simon J, Barbier-Torres L, Gomez-Santos B, et al. miR-873-5p targets mitochondrial GNMT-Complex II interface contributing to non-alcoholic fatty liver disease. Mol Metab. 2019;29:40-54. https://doi.org/10.1016/j.molmet.2019.08.008
27. Song YH, Shiota M, Kuroiwa K, Naito S, Oda Y. The important role of glycine N-methyltransferase in the carcinogenesis and progression of prostate cancer. Mod Pathol. 2011;24(9):1272-80. https://doi.org/10.1038/modpathol.2011.76
28. Miao L, Liu Y, Chen W, Gao C, Zhang Y, Wei J, et al. Brucine Suppresses Malignant Progression of Prostate Cancer by Decreasing Sarcosine Accumulation via Downregulation of GNMT in the Glycine/sarcosine Metabolic Pathway. Cell Biochem Biophys. 2024;82(3):2373-85. https://doi.org/10.1007/s12013-024-01348-z
29. Zabala-Letona A, Arruabarrena-Aristorena A, Fernandez-Ruiz S, Viera C, Carlevaris O, Ercilla A, et al. PI3K-regulated Glycine N-methyltransferase is required for the development of prostate cancer. Oncogenesis. 2022;11(1):10. https://doi.org/10.1038/s41389-022-00382-x
30. Bianchi F, Dugheri S, Musci M, Bonacchi A, Salvadori E, Arcangeli G, et al. Fully automated solid-phase microextraction-fast gas chromatography-mass spectrometry method using a new ionic liquid column for high-throughput analysis of sarcosine and N-ethylglycine in human urine and urinary sediments. Anal Chim Acta. 2011;707(1-2):197-203. https://doi.org/10.1016/j.aca.2011.09.015
31. Yamkamon V, Yee PP, Yainoi S, Eiamphungporn W, Suksrichavalit T. Simultaneous determination of sarcosine and its related metabolites by gas chromatography-tandem mass spectrometry for prostate cancer diagnosis. EXCLI J. 2018;17:965-79. https://doi.org/10.17179/excli2018-1352
32. Passornraprasit N, Hinestroza JP, Rodthongkum N, Potiyaraj P. Cellulose nanofibers/polyacrylic acid hydrogels integrated with a 3D printed strip: A platform for screening prostate cancer via sarcosine detection. Carbohydr Polym. 2025;352:123134. https://doi.org/10.1016/j.carbpol.2024.123134
33. Markin PA, Brito A, Moskaleva N, Fodor M, Lartsova EV, Shpot YV, et al. Plasma Sarcosine Measured by Gas Chromatography-Mass Spectrometry Distinguishes Prostatic Intraepithelial Neoplasia and Prostate Cancer from Benign Prostate Hyperplasia. Lab Med. 2020;51(6):566-73. https://doi.org/10.1093/labmed/lmaa008
| Files | ||
| Issue | Vol 2 No 4 (2024) | |
| Section | Original Articles | |
| Keywords | ||
| Prostate cancer Glycine N-methyltransferase benign prostatic hyperplasia | ||
| Rights and permissions | |
|
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Esmaili E, Khalaj F, Shafee H, Ranaee M, Halalkhor S, Samavarchi Tehrani S. Comparison of the serum level of glycine N-methyl transferase (GNMT) enzyme in prostate cancer, benign prostatic hyperplasi and healthy subjects. ABI. 2024;2(4):221-226.
