Eser KILIÇ, Oğuz Galip YILDIZ, Hatice SARAÇOĞLU, Nazlı HELVACI

The study of sirtuins in breast cancer patients before and after radiotherapy

Background/aim: Targeting the new and unique proteins is an important medical strategy for treating breast cancer. It is quite important to find out proteins that have a role in the development of cancer. Sirtuins (SIRT) are well related in different physiological activities and connected with cancer. We aimed to determine the effect of radiotherapy on SIRT1 and SIRT2, which have not been yet been clarified as a tumor suppressor or promoter.Materials and methods: Twenty-two women with nonmetastatic breast cancer enrolled in the study. Blood samples were taken before and after radiotherapy, soluble SIRT1 and SIRT2 levels were determined with ELISA kits.Results: There was no difference in SIRT1 levels before and after radiotherapy (p = 0.548). SIRT2 levels were significantly found to be decreased after radiotherapy (p = 0.042). There was a strong and positive correlation before radiotherapy (p < 0.001), and a moderate and positive correlation after radiotherapy (p = 0.007) between SIRT1 and SIRT2.Conclusion: These results suggest that SIRT2 may provide a new strategy for follow-up of breast cancer treatment. Additionally, by emphasizing the importance of SIRT2 in breast cancer, it opens ways to provide grounds for the development of the next generation of SIRT2-specific radiotracers. Finally, the most important thing, in fact, the positive correlation between SIRT1 and SIRT2 both before and after radiotherapy, appears to be clear evidence suggesting more oncogenic roles of sirtuins.Key words: Sirtuin, breast cancer, radiotherapy

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1. Sparano JA, Fazzari MJ, Childs G. Clinical application of molecular profiling in breast cancer. Future Oncology 2015; 1 (4): 485-496. doi: 10.2217/14796694.1.4.485
2. Boyages J, Baker L. Evolution of radiotherapy techniques in breast conservation treatment. Gland Surgery 2018; 7 (6): 576-595. doi: 10.21037/gs.2018.11.10
3. O’Sullivan CC, Loprinzi CL, Haddad TC. Updates in the evaluation and management of breast cancer. Mayo Clinic Proceedings 2018; 93 (6): 794-807. doi: 10.1016/j. mayocp.2018.03.025
4. Zhou Z, Ma T, Zhu Q, Xu Y, Zha X. Recent advances in inhibitors of sirtuin1/2: an update and perspective. Future Medicinal Chemistry 2018; 10 (8): 907-934. doi: 10.4155/fmc2017-0207
5. Ong ALC, Ramasamy TS. Role of Sirtuin1-p53 regulatory axis in aging, cancer and cellular reprogramming. Ageing Research Reviews 2018; 43: 64-80. doi: 10.1016/j.arr.2018.02.004
6. Zhang W, Liu D, Ren J, Zhou P, Han X. Overexpression of Sirtuin2 prevents high glucose-induced vascular endothelial cell injury by regulating the p53 and NF-κB signaling pathways. Biotechnology Letters 2018; 40 (2): 271-278. doi: 10.1007/ s10529-017-2487-y
7. Karbasforooshan H, Roohbakhsh A, Karimi G. SIRT1 and microRNAs: the role in breast, lung and prostate cancers. Experimental Cell Research 2018; 367 (1): 1-6. doi: 10.1016/j. yexcr.2018.03.023
8. Jiang Y, Liu J, Chen D, Yan L, Zheng W. Sirtuin inhibition: strategies, inhibitors, and therapeutic potential. Trends in Pharmacological Sciences 2017; 38 (5): 459-472. doi: 10.1016/j. tips.2017.01.009
9. Mei Z, Zhang X, Yi J, Huang J, He J et al. Sirtuins in metabolism, DNA repair and cancer. Journal of Experimental & Clinical Cancer Research 2016; 35( 1): 182. doi: 10.1186/s13046-016- 0461-5
10. Kratz EM, Sołkiewicz K, Kubis-Kubiak A, Piwowar A. Sirtuins as important factors in pathological states and the role of their molecular activity modulators. International Journal of Molecular Sciences 2021; 22 (2): 630. doi: 10.3390/ ijms22020630
11. Kleszcz R, Paluszczak J, Baer-Dubowska W. Targeting aberrant cancer metabolism - the role of sirtuins. Pharmacological Reports 2015; 67 (6): 1068-1080. doi: 10.1016/j.pharep.2015.03.021
12. Choi JE, Mostoslavsky R. Sirtuins, metabolism, and DNA repair. Current Opinion in Genetics & Development 2014; 26: 24-32. doi: 10.1186/s13046-016-0461-5
13. Lin Z, Fang D. The roles of SIRT1 in cancer. Genes and Cancer 2013; 4 (3-4): 97-104. doi: 10.1177/1947601912475079
14. Zhao E, Hou J, Ke X, Abbas MN, Kausar S et al. The roles of sirtuin family proteins in cancer progression. Cancers (Basel). 2019; 11 (12): 1949. doi:10.3390/cancers11121949
15. Fang Y, Nicholl MB. A dual role for sirtuin 1 in tumorigenesis. Current Pharmaceutical Design 2014; 20 (15): 2634-2636. doi: 10.2174/13816128113199990488
16. Roth M, Chen WY. Sorting out functions of sirtuins in cancer. Oncogene 2014; 33 (13): 1609-1620. doi: 10.1038/onc.2013.120
17. Sebastian C, Satterstrom FK, Haigis MC, Mostoslavsky R. From sirtuin biology to human diseases: an update. Journal of Biological Chemistry 2012; 287 (51): 42444-42452. doi: 10.1074/jbc.R112.402768
18. De Oliveira RM, Sarkander J, Kazantsev AG, Outeiro TF. SIRT2 as a therapeutic target for age-related disorders. Frontiers in Pharmacology 2012; 3: 82. doi: 10.3389/fphar.2012.00082
19. Martinez-Pastor B, Mostoslavsky R. Sirtuins, metabolism, and cancer. Frontiers in Pharmacology 2012; 21; 3: 22. doi: 10.3389/fphar.2012.00022
20. Wang J, Cai Y, Sheng Z. Experimental studies on the protective effects of the overexpression of lentivirusmediated sirtuin 6 on radiation-induced lung injury. Advances in Clinical and Experimental Medicine 2020; 29 (7): 873-877. doi: 10.17219/acem/117685
21. Sun C, Zeng X, Guo H, Wang T, Wei L et al. MicroRNA-125a5p modulates radioresistance in LTEP-a2 non-small cell lung cancer cells by targeting SIRT7. Cancer Biomarkers 2020; 27 (1): 39-49. doi: 10.3233/CBM-190381
22. Zhang X, Li Y, Wang D, Wei X. miR-22 suppresses tumorigenesis and improves radiosensitivity of breast cancer cells by targeting Sirt1. Biological Research 2017; 50 (1): 27. doi: 10.1186/s40659-017-0133-8
23. Tang M, Lu X, Zhang C, Du C, Cao L et al. Downregulation of SIRT7 by 5-fluorouracil induces radiosensitivity in human colorectal cancer. Theranostics 2017; 7 (5): 1346-1359. doi: 10.7150/thno.18804
24. Alhazzazi TY, Kamarajan P, Joo N, Huang JY, Verdin E et al. Sirtuin-3 (SIRT3), a novel potential therapeutic target for oral cancer. Cancer 2011; 117 (8): 1670-1678. doi: 10.1002/ cncr.25676
25. McGlynn LM, Zino S, MacDonald AI, Curle J, Reilly JE et al. SIRT2: tumour suppressor or tumour promoter in operable breast cancer? European Journal of Cancer 2014; 50 (2): 290- 301. doi: 10.1016/j.ejca.2013.10.005
26. Voelter-Mahlknecht S, Mahlknecht U. The sirtuins in the pathogenesis of cancer. Clinical Epigenetics 2010; 1 (3-4): 71- 83. doi: 10.1007/s13148-010-0008-0
27. Inoue T, Hiratsuka M, Osaki M, Oshimura M. The molecular biology of mammalian SIRT proteins: SIRT2 in cell cycle regulation. Cell Cycle 2007; 2; 6 (9): 1011-1018. doi: 10.4161/cc.6.9.4219
28. Horio Y, Hayashi T, Kuno A, Kunimoto R. Cellular and molecular effects of sirtuins in health and disease. Clinical Science (London) 2011; 121 (5): 191-203. doi: 10.1042/CS20100587
29. Liu PY, Xu N, Malyukova A, Scarlett CJ, Sun YT et al. The histone deacetylase SIRT2 stabilizes Myc oncoproteins. Cell Death and Differentiation 2013; 20 (3): 503-514. doi: 10.1038/ cdd.2012.147