Annals of the Russian academy of medical sciencesAnnals of the Russian academy of medical sciencesВестник Российской академии медицинских наук0869-60472414-3545"Paediatrician" Publishers LLC224210.15690/vramn2242ONCOLOGY: CURRENT ISSUESАКТУАЛЬНЫЕ ВОПРОСЫ ОНКОЛОГИИReview ArticleAntiaging Klotho Protein as a Prospective Novel Tumor SuppressorАнтивозрастной белок Клото как новый потенциальный супрессор опухолевого ростаhttps://orcid.org/0000-0001-6377-7552NesterovaKristina I.НестероваКристина Игоревна
Canada

MD, Medical Resident, Internal Medicine PGY-1

врач-терапевт, резидент программы «Внутренние болезни»

kristinachka2013@gmail.comhttps://orcid.org/0000-0003-0187-2559GlinkaYelena Yu.ГлинкаЕлена Юрьевна
Canada

Researcher

исследователь

pyat57@rogers.comhttps://orcid.org/0000-0002-2457-84866256153291-9904PerfilovaValentina N.ПерфиловаВалентина Николаевна
Russian Federation

PhD in Biology, Professor

д.б.н., профессор

vnperfilova@mail.ruhttps://orcid.org/0000-0001-7249-39066438625640-5539NesterovaAlla A.НестероваАлла Анатольевна
Russian Federation

MD, PhD, Associate Professor

к.м.н., доцент

aanesterova2013@gmail.comhttps://orcid.org/0000-0001-6574-05185051-9022KaplanovKamil D.КаплановКамиль Даниялович
Russian Federation

MD, PhD

к.м.н.

kamil.kaplanov75@gmail.comUniversity of TorontoУниверситет ТоронтоKeenan Research Centre, St. Michael’s HospitalИсследовательский центр Кинана, больница св. МихаилаVolgograd State Medical UniversityВолгоградский государственный медицинский университетCity Clinical Hospital Named after S.P. BotkinГородская клиническая больница им. С.П. Боткина160220230403202378124441110202203022023Copyright ©; 2023, "Paediatrician" Publishers LLCCopyright ©; 2023, Издательство "Педиатръ"2023"Paediatrician" Publishers LLCИздательство "Педиатръ"https://vestnikramn.spr-journal.ru/jour/about/submissionshttps://vestnikramn.spr-journal.ru/jour/article/view/2242

α-Isomer of Klotho Protein has been actively studied over the past 20 years. It has been found that α-Klotho is closely associated with aging and has anti-aging properties. Besides, it is involved in development of malignant tumor diseases. Its universal influence on many biological mechanisms leading to hyperplastic changes in cells and tissues has been proven experimentally. Recent studies demonstrated inhibitory effect of α-Klotho on the classical carcinogenic pathways such as insulin-like growth factor 1 (IGF1), fibroblast growth factor (FGFs), transforming growth factor β1 (TGFb1), Wnt, P53/p21, oxidative stress response pathways. Impeding effect of α-Klotho protein on the development of such types of malignant tumors as breast, pancreatic, lung, stomach, hepatocarcinoma, and others is proven in a number of cases. This review describes the role of α-Klotho in oncogenesis, its involvement and influence on the main signaling pathways known for their role in the development of malignant tumors, and the possibility of regulating its expression.

С момента своего открытия 20 лет назад белок Клото активно изучается во всем мире. Выявлено, что его изомер α-Клото тесно связан с процессами старения и обладает антивозрастными свойствами. В экспериментальных работах было показано, что α-Клото универсально воздействует на многие биологические механизмы, ведущие к гиперпластическим изменениям клеток и тканей, ингибирует известные канцерогенные пути с вовлечением инсулиноподобного фактора роста 1 (IGF1), фактора роста фибробластов (FGFs), трансформирующего фактора роста β1 (TGFb1), Wnt, P53/p21, а также воздействует на путь окислительного стресса (oxidative stress response). Все больше научных данных указывает на то, что белок Клото влияет на развитие таких видов злокачественных опухолей, как рак молочной и поджелудочной желез, легких, желудка, гепатокарциномы и др. В данном обзоре рассматривается роль α-Клото в онкогенезе, его влияние на основные сигнальные пути развития злокачественных опухолей и возможности регуляции его экспрессии.

KlothocarcinogenesissignalingКлотоканцерогенезсигнальный путьKuro-o M, Matsumura Y, Aizawa H, et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature. 1997;390(6655):45–51. doi: https://doi.org/10.1038/36285Нестерова А.А., Глинка Е.Ю., Тюренков И.Н., и др. Белок клото — универсальный регулятор физиологических процессов в организме // Успехи физиологических наук. — 2020. — Т. 51. — № 2. — С. 88–104. [Nesterova AA, Glinka EYu, Tyurenkov IN, et al. Universal Protein Klotho — Regulator of Physiological Processes in the Organism. Uspekhi fiziologicheskih nauk. 2020;51(2): 88–104. (In Russ.)] doi: https://doi.org/10.31857/S0301179820020083Xie B, Chen J, Liu B, et al. Klotho acts as a tumor suppressor in cancers. Pathol Oncol Res. 2013;19(4):611–617. doi: https://doi.org/10.1007/s12253-013-9663-8GLOBOCAN 2021: estimated cancer incidence, mortality and prevalence worldwide in 2020.White MC, Holman DM, Boehm JE, et al. Age and cancer risk: A potentially modifiable relationship. Am J Prev Med. 2014;46(3Suppl1):S7–15. doi: https://doi.org/10.1016/j.amepre.2013.10.029Berben L, Floris G, Wildiers H, et al. Cancer and Aging: Two Tightly Interconnected Biological Processes. Cancers (Basel). 2021;13(6):1400. doi: https://doi.org/10.3390/cancers13061400Siametis A, Niotis G, Garinis GA. DNA Damage and the Aging Epigenome. J Invest Dermatol. 2021;141(4S):961–967. doi: https://doi.org/10.1016/j.jid.2020.10.006Patel J, Baptiste BA, Kim E, et al. DNA damage and mitochondria in cancer and aging. Carcinogenesis. 2020;41(12):1625–1634. doi: https://doi.org/10.1093/carcin/bgaa114Negrini S, Gorgoulis VG, Halazonetis TD. Genomic instability — an evolving hallmark of cancer. Nat Rev Mol Cell Biol. 2010;11(3):220–228. doi: https://doi.org/10.1038/nrm2858Xu Y, Sun Z. Molecular basis of Klotho: From gene to function in aging. Endocr Rev. 2015;36(2):174–193. doi: https://doi.org/10.1210/er.2013-1079Wang Y, Sun Z. Current understanding of klotho. Ageing Res Rev. 2009;8(1):43–51. doi: https://doi.org/10.1016/j.arr.2008.10.002Tyurenkov IN, Perfilova VN, Nesterova AA, et al. Klotho Protein and Cardio-Vascular System. Biochemistry (Mosc). 2021;86(2):132–145. doi: https://doi.org/10.1134/S0006297921020024Tohyama O, Imura A, Iwano A, et al. Klotho is a novel beta-glucuronidase capable of hydrolyzing steroid beta-glucuronides. J Biol Chem. 2004;279(11):9777–9784. doi: https://doi.org/10.1074/jbc.M312392200Chen CD, Podvin S, Gillespie E, et al. Insulin stimulates the cleavage and release of the extracellular domain of Klotho by ADAM10 and ADAM17. Proc Natl Acad Sci U S A. 2007;104(50):19796–19801. doi: https://doi.org/10.1073/pnas.0709805104Lim K, Groen A, Molostvov G, et al. α-Klotho Expression in Human Tissues. J Clin Endocrinol Metab. 2015;100(10):E1308–E1318. doi: https://doi.org/10.1210/jc.2015-1800Lim K, Halim A, Lu T-S, et al. Klotho: A Major Shareholder in Vascular Aging Enterprises. Int J Mol Sci. 2019;20(18):4637. doi: https://doi.org/10.3390/ijms20184637Bian A, Neyra JA, Zhan M, et al. Klotho, stem cells, and aging. Clin Interv Aging. 2015;10:1233–1243. doi: https://doi.org/10.2147/CIA.S84978Turan K, Ata P. Effects of intra- and extracellular factors on anti-aging klotho gene expression. Genet Mol Res. 2011;10(3):2009–2023. doi: https://doi.org/10.4238/vol10-3gmr1261Matsumura Y, Aizawa H, Shiraki-Iida T, et al. Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein. Biochem Biophys Res Commun. 1998;242(3):626–630. doi: https://doi.org/10.1006/bbrc.1997.8019King GD, Rosene DL, Abraham CR. Promoter methylation and age-related downregulation of Klotho in rhesus monkey. Age (Dordr). 2012;34(6):1405–1419. doi: https://doi.org/10.1007/s11357-011-9315-4Azuma M, Koyama D, Kikuchi J, et al. Promoter methylation confers kidney-specific expression of the Klotho gene. FASEB J. 2012;26(10):4264–4274. doi: https://doi.org/10.1096/fj.12-211631Young G-H, Wu V-C. KLOTHO methylation is linked to uremic toxins and chronic kidney disease. Kidney Int. 2012;81(7):611–612. doi: https://doi.org/10.1038/ki.2011.461Wang L, Wang X, Wang X, et al. Klotho is silenced through promoter hypermethylation in gastric cancer. Am J Cancer Res. 2011;1(1):111–119.Xu T-H, Liu M, Zhou XE, et al. Structure of nucleosome-bound DNA methyltransferases DNMT3A and DNMT3B. Nature. 2020; 586(7827):151–155. doi: https://doi.org/10.1038/s41586-020-2747-1Zhang Z-M, Lu R, Wang P, et al. Structural basis for DNMT3A-mediated de novo DNA methylation. Nature. 2018;554(7692):387–391. doi: https://doi.org/10.1038/nature25477Pacaud R, Sery Q, Oliver L, et al. DNMT3L interacts with transcription factors to target DNMT3L/DNMT3B to specific DNA sequences: role of the DNMT3L/DNMT3B/p65-NFκB complex in the (de-)methylation of TRAF1. Biochimie. 2014;104:36–49. doi: https://doi.org/10.1016/j.biochi.2014.05.005Senyuk V, Premanand K, Xu P, et al. The oncoprotein EVI1 and the DNA methyltransferase Dnmt3 co-operate in binding and de novo methylation of target DNA. PLoS One. 2011;6(6):e20793. doi: https://doi.org/10.1371/journal.pone.0020793Tataranni T, Biondi G, Cariello M, et al. Rapamycin-induced hypophosphatemia and insulin resistance are associated with mTORC2 activation and Klotho expression. Am J Transplant. 2011;11(8):1656–1664. doi: https://doi.org/10.1111/j.1600-6143.2011.03590.xKing GD, Chen C, Huang MM, et al. Identification of novel small molecules that elevate Klotho expression. Biochem J. 2012;441(1):453–461. doi: https://doi.org/10.1042/BJ20101909Mizuno I, Takahashi Y, Okimura Y, et al. Upregulation of the klotho gene expression by thyroid hormone and during adipose differentiation in 3T3-L1 adipocytes. Life Sci. 2001;68(26):2917–2923. doi: https://doi.org/10.1016/s0024-3205(01)01092-xMehi SJ, Maltare A, Abraham CR, et al. MicroRNA-339 and microRNA-556 regulate Klotho expression in vitro. Age (Dordr). 2014;36(1):141–149. doi: https://doi.org/10.1007/s11357-013-9555-6Hawkins PG, Morris KV. RNA and transcriptional modulation of gene expression. Cell Cycle. 2008;7(5):602–607. doi: https://doi.org/10.4161/cc.7.5.5522Yoon HE, Ghee JY, Piao S, et al. Angiotensin II blockade upregulates the expression of Klotho, the anti-ageing gene, in an experimental model of chronic cyclosporine nephropathy. Nephrol Dial Transplant. 2011;26(3):800–813. doi: https://doi.org/10.1093/ndt/gfq537Wolf G, Wenzel U, Burns KD, et al. Angiotensin II activates nuclear transcription factor-kappaB through AT1 and AT2 receptors. Kidney Int. 2002;61(6):1986–1995. doi: https://doi.org/10.1046/j.1523-1755.2002.00365.xMitobe M, Yoshida T, Sugiura H, et al. Oxidative stress decreases klotho expression in a mouse kidney cell line. Nephron Exp Nephrol. 2005;101(2):e67–e74. doi: https://doi.org/10.1159/000086500Shimizu H, Bolati D, Adijiang A, et al. Indoxyl sulfate downregulates 2renal expression of Klotho through production of ROS and activation of nuclear factor-kB. Am J Nephrol. 2011;33(4):319–324. doi: https://doi.org/10.1159/000324885Saito K, Ishizaka N, Mitani H, et al. Iron chelation and a free radical scavenger suppress angiotensin II-induced downregulation of klotho, an anti-aging gene, in rat. FEBS Lett. 2003;551(1–3):58–62. doi: https://doi.org/10.1016/s0014-5793(03)00894-9Behera R, Kaur A, Webster MR, et al. Inhibition of Age-Related Therapy Resistance in Melanoma by Rosiglitazone-Mediated Induction of Klotho. Clin Cancer Res. 2017;23(12):3181–3190. doi: https://doi.org/10.1158/1078-0432.CCR-17-0201Ewendt F, Feger M, Föller M. Role of Fibroblast Growth Factor 23 (FGF23) and αKlotho in Cancer. Front Cell Dev Biol. 2021;8:601006. doi: https://doi.org/10.3389/fcell.2020.601006Zhou Q, Lin S, Tang R, et al. Role of Fosinopril and Valsartan on Klotho Gene Expression Induced by Angiotensin II in Rat Renal Tubular Epithelial Cells. Kidney Blood Press Res. 2010;33(3):186–192. doi: https://doi.org/10.1159/000316703Tang R, Zhou Q-L, Ao X, et al. Fosinopril and losartan regulate klotho gene and nicotinamide adenine dinucleotide phosphate oxidase expression in kidneys of spontaneously hypertensive rats. Kidney Blood Press Res. 2011;34(5):350–357. doi: https://doi.org/10.1159/000326806Mencke R, Harms G, Moser J, et al. Human alternative Klotho mRNA is a nonsense-mediated mRNA decay target inefficiently spliced in renal disease. JCI Insight. 2017;2(20):e94375. doi: https://doi.org/10.1172/jci.insight.94375Chen G, Liu Y, Goetz R, et al. α-Klotho is a non-enzymatic molecular scaffold for FGF23 hormone signalling. Nature. 2018;553(7689):461–466. doi: https://doi.org/10.1038/nature25451Xie B, Zhou J, Shu G, et al. Restoration of klotho gene expression induces apoptosis and autophagy in gastric cancer cells: tumor suppressive role of klotho in gastric cancer. Cancer Cell Int. 2013;13(1):18. doi: https://doi.org/10.1186/1475-2867-13-18Qu Y, Dang S, Hou P. Gene methylation in gastric cancer. Clin Chim Acta. 2013;424:53–65. doi: https://doi.org/10.1016/j.cca.2013.05.002Tang X, Fan Z, Wang Y, et al. Expression of klotho and β-catenin in esophageal squamous cell carcinoma, and their clinicopathological and prognostic significance. Dis Esophagus. 2016;29(3):207–214. doi: https://doi.org/10.1111/dote.12289Abramovitz L, Rubinek T, Ligumsky H, et al. KL1 internal repeat mediates klotho tumor suppressor activities and inhibits bFGF and IGF-I signaling in pancreatic cancer. Clin Cancer Res. 2011;17(13):4254–4266. doi: https://doi.org/10.1158/1078-0432.CCR-10-2749Arbel Rubinstein T, Reuveni I, Hesin A, et al. A transgenic model reveals the role of Klotho in pancreatic cancer development and paves the way for new Klotho-based Therapy. Cancers (Basel). 2021;13(24):6297. doi: https://doi.org/10.3390/cancers13246297Tang X, Wang Y, Fan Z, et al. Klotho: a tumor suppressor and modulator of the Wnt/β-catenin pathway in human hepatocellular carcinoma. Lab Invest. 2016;96(2):197–205. doi: https://doi.org/10.1038/labinvestSun H, Gao Y, Lu K, et al. Overexpression of Klotho suppresses liver cancer progression and induces cell apoptosis by negatively regulating wnt/β-catenin signaling pathway. World J Surg Oncol. 2015;13:307. doi: https://doi.org/10.1186/s12957-015-0717-0He X-J, Ma Y-Y, Yu S, et al. Up-regulated miR-199a-5p in gastric cancer functions as an oncogene and targets klotho. BMC Cancer. 2014;14:218. doi: https://doi.org/10.1186/1471-2407-14-218Calin GA, Sevignani C, Dumitru CD, et al. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci U S A. 2004;101(9):2999–3004. doi: https://doi.org/10.1073/pnas.0307323101Pan J, Zhong J, Gan LH, et al. Klotho, an anti-senescence related gene, is frequently inactivated through promoter hypermethylation in colorectal cancer. Tumour Biol. 2011;32(4):729–735. doi: https://doi.org/10.1007/s13277-011-0174-5Arbel Rubinstein T, Shahmoon S, Zigmond E, et al. Klotho suppresses colorectal cancer through modulation of the unfolded protein response. Oncogene. 2019;38(6):794–807. doi: https://doi.org/10.1038/s41388-018-0489-4Li X-X, Huang L-Y, Peng J-J, et al. Klotho suppresses growth and invasion of colon cancer cells through inhibition of IGF1R-mediated PI3K/AKT pathway. Int J Oncol. 2014;45(2):611–618. doi: https://doi.org/10.3892/ijo.2014.2430Li Q, Li Y, Liang L, et al. Klotho negatively regulated aerobic glycolysis in colorectal cancer via ERK/HIF1α axis. Cell Commun Signal. 2018;16(1):26. doi: https://doi.org/10.1186/s12964-018-0241-2Liu Y, Pan J, Pan X, et al. Klotho-mediated targeting of CCL2 suppresses the induction of colorectal cancer progression by stromal cell senescent microenvironments. Mol Oncol. 2019;13(11):2460–2475. doi: https://doi.org/10.1002/1878-0261.12577Shu G, Xie B, Ren F, et al. Restoration of klotho expression induces apoptosis and autophagy in hepatocellular carcinoma cells. Cell Oncol (Dordr). 2013;36(2):121–129. doi: https://doi.org/10.1007/s13402-012-0118-0Chen L, Liu H, Liu J, et al. Klotho endows hepatoma cells with resistance to anoikis via VEGFR2/PAK1 activation in hepatocellular carcinoma. PLoS One. 2013;8(3):e58413. doi: https://doi.org/10.1371/journal.pone.0058413Hernandez-Gea V, Toffanin S, Friedman SL, et al. Role of the microenvironment in the pathogenesis and treatment of hepatocellular carcinoma. Gastroenterology. 2013;144(3):512–527. doi: https://doi.org/10.1053/j.gastro.2013.01.002Jiang B, Gu Y, Chen Y. Identification of novel predictive markers for the prognosis of pancreatic ductal adenocarcinoma. Cancer Invest. 2014;32(6):218–225. doi: https://doi.org/10.3109/07357907.2014.905586Zhang G, Zhai N, Zhang X. Alkannin represses growth of pancreatic cancer cells based on the down regulation of miR-199a. Biofactors. 2020;46(5):849–859. doi: https://doi.org/10.1002/biof.1613Chen B, Wang X, Zhao W, et al. Klotho inhibits growth and promotes apoptosis in human lung cancer cell line A549. J Exp Clin Cancer Res. 2010;29(1):99. doi: https://doi.org/10.1186/1756-9966-29-99Chen B., Ma X, Liu Sh, et al. Inhibition of lung cancer cells growth, motility and induction of apoptosis by Klotho, a novel secreted Wnt antagonist, in a dose-dependent manner. Cancer Biol Ther. 2012;13(12):1221–1228. doi: https://doi.org/10.4161/cbt.21420Chen B, Liang Y, Chen L, et al. Overexpression of Klotho Inhibits HELF Fibroblasts SASP-related Protumoral Effects on Non-small Cell Lung Cancer Cells. J Cancer. 2018;9(7):1248–1258. doi: https://doi.org/10.7150/jca.23967Usuda J, Ichinose S, Ishizumi T, et al. Klotho predicts good clinical outcome in patients with limited-disease small cell lung cancer who received surgery. Lung Cancer. 2011;74(2):332–337. doi: https://doi.org/10.1016/j.lungcan.2011.03.004Brominska B, Gabryel P, Jarmołowska-Jurczyszyn D, et al. Klotho expression and nodal involvement as predictive factors for large cell lung carcinoma. Arch Med Sci. 2019;15(4):1010–1016. doi: https://doi.org/10.5114/aoms.2018.75889Ibi T, Usuda J, Inoue T, et al. Klotho expression is correlated to molecules associated with epithelial-mesenchymal transition in lung squamous cell carcinoma. Oncol Lett. 2017;14(5):5526–5532. doi: https://doi.org/10.3892/ol.2017.6862Pako J, Bikov A, Barta I, et al. Assessment of the circulating klotho protein in lung cancer patients. Pathol Oncol Res. 2020;26(1):233–238. doi: https://doi.org/10.1007/s12253-018-0441-5Wang Y, Chen L, Huang G, et al. Klotho sensitizes human lung cancer cell line to cisplatin via PI3k/Akt pathway. PLoS One. 2013;8(2):e57391. doi: https://doi.org/10.1371/journal.pone.0057391Chen T, Ren H, Thakur A, et al. Decreased Level of Klotho Contributes to Drug Resistance in Lung Cancer Cells: Involving in Klotho-Mediated Cell Autophagy. DNA Cell Biol. 2016;35(12):751–757. doi: https://doi.org/10.1089/dna.2016.3437Lu L, Katsaros D, Wiley A, et al. Klotho expression in epithelial ovarian cancer and its association with insulin-like growth factors and disease progression. Cancer Invest. 2008;26(2):185–192. doi: https://doi.org/10.1080/07357900701638343Lojkin I, Rubinek T, Orsulic S, et al. Reduced expression and growth inhibitory activity of the aging suppressor klotho in epithelial ovarian cancer. Cancer Lett. 2015;362(2):149–157. doi: https://doi.org/10.1016/j.canlet.2015.03.035Yan Y, Wang Y, Xiong Y, et al. Reduced Klotho expression contributes to poor survival rates in human patients with ovarian cancer, and overexpression of Klotho inhibits the progression of ovarian cancer partly via the inhibition of systemic inflammation in nude mice. Mol Med Rep. 2017;15(4):1777–1785. doi: https://doi.org/10.3892/mmr.2017.6172Aviel-Ronen S, Rubinek T, Zadok O, et al. Klotho expression in cervical cancer: differential expression in adenocarcinoma and squa-mous cell carcinoma. J Clin Pathol. 2016;69(1):53–57. doi: https://doi.org/10.1136/jclinpath-2015-202929Lee J, Jeong D-J, Kim J, et al. The anti-aging gene KLOTHO is a novel target for epigenetic silencing in human cervical carcinoma. Mol Cancer. 2010;9:109. doi: https://doi.org/10.1186/1476-4598-9-109Qureshi R, Arora H, Rizvi MA. EMT in cervical cancer: Its role in tumour progression and response to therapy. Cancer Lett. 2015;356(2 Pt B):321–331. doi: https://doi.org/10.1016/j.canlet.2014.09.021Wolf I, Levanon-Cohen S, Bose S, et al. Klotho: a tumor suppressor and a modulator of the IGF-1 and FGF pathways in human breast cancer. Oncogene. 2008;27(56):7094–7105. doi: 10.1038/onc.2008.292Fenig E, Szyper-Kravitz M, Yerushalmi R, et al. Basic fibroblast growth factor mediated growth inhibition in breast cancer cells is independent of ras signaling pathway. Oncol Rep. 2002;9(4):875-877.Korah RM, Sysounthone V, Golowa Y, et al. Basic fibroblast growth factor confers a less malignant phenotype in MDA-MB-231 human breast cancer cells. Cancer Res. 2000;60(3):733–740.Lim SW, Jin L, Luo K, et al. Klotho enhances FoxO3-mediated manganese superoxide dismutase expression by negatively regulating PI3K/AKT pathway during tacrolimus-induced oxidative stress. Cell Death Dis. 2017;8(8):e2972. doi: https://doi.org/10.1038/cddis.2017.365Rubinek T, Shulman M, Israeli S, et al. Epigenetic silencing of the tumor suppressor klotho in human breast cancer. Breast Cancer Res Treat. 2012;133(2):649–657. doi: https://doi.org/10.1007/s10549-011-1824-4Ligumsky H, Rubinek T, Merenbakh-Lamin K, et al. Tumor Suppressor Activity of Klotho in Breast Cancer Is Revealed by Structure-Function Analysis. Mol Cancer Res. 2015;13(10):1398–1407. doi: https://doi.org/10.1158/1541-7786.MCR-15-0141Shmulevich R, Nissim TB, Wolf I, et al. Klotho rewires cellular metabolism of breast cancer cells through alteration of calcium shuttling and mitochondrial activity. Oncogene. 2020;39(24):4636–4649. doi: https://doi.org/10.1038/s41388-020-1313-5Wolf I, Laitman Y, Rubinek T, et al. Functional variant of KLOTHO: a breast cancer risk modifier among BRCA1 mutation carriers of Ashkenazi origin. Oncogene. 2010;29(1):26–33. doi: https://doi.org/10.1038/onc.2009.301Zhu Y, Xu L, Zhang J, et al. Klotho suppresses tumor progression via inhibiting PI3K/Akt/GSK3β/Snail signaling in renal cell carcinoma. Cancer Sci. 2013;104(6):663–671. doi: https://doi.org/10.1111/cas.12134Gigante M, Lucarelli G, Divella C, et al. Soluble Serum αKlotho Is a Potential Predictive Marker of Disease Progression in Clear Cell Renal Cell Carcinoma. Medicine (Baltimore). 2015;94(45):e1917. doi: https://doi.org/10.1097/MD.0000000000001917Kim J-H, Hwang K-H, Lkhagvadorj S, et al. Klotho plays a critical role in clear cell renal cell carcinoma progression and clinical outcome. Korean J Physiol Pharmacol. 2016;20(3):297–304. doi: https://doi.org/10.4196/kjpp.2016.20.3.297Hori S, Miyake M, Onishi S, et al. Clinical significance of α and βKlotho in urothelial carcinoma of the bladder. Oncol Rep. 2016;36(4):2117–2125. doi: https://doi.org/10.3892/or.2016.5053Camilli TC, Xu M, O’Connell MP, et al. Loss of Klotho during melanoma progression leads to increased filamin cleavage, increased Wnt5A expression, and enhanced melanoma cell motility. Pigment Cell Melanoma Res. 2011;24(1):175–186. doi: https://doi.org/10.1111/j.1755-148X.2010.00792.xDelcroix V, Mauduit O, Tessier N, et al. The Role of the Anti-Aging Protein Klotho in IGF-1 Signaling and Reticular Calcium Leak: Impact on the Chemosensitivity of Dedifferentiated Liposarcomas. Cancers (Basel). 2018;10(11):439. doi: https://doi.org/10.3390/cancers10110439Shen B, Kwan H-Y, Ma X, et al. cAMP activates TRPC6 channels via the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (PKB)-mitogen-activated protein kinase kinase (MEK)-ERK1/2 signaling pathway. J Biol Chem. 2011;286(22):19439–19445. doi: https://doi.org/10.1074/jbc.M110.210294Li Y, Xiao H-J, Xue F. Overexpression of klotho suppresses growth and pulmonary metastasis of osteosarcoma in vivo. Genet Mol Biol. 2020;43(2):e20190229. doi: https://doi.org/10.1590/1678-4685-GMB-2019-0229Peshes-Yeloz N, Ungar L, Wohl A, et al. Role of Klotho Protein in Tumor Genesis, Cancer Progression, and Prognosis in Patients with High-Grade Glioma. World Neurosurg. 2019;130:e324–e332. doi: https://doi.org/10.1016/j.wneu.2019.06.082Zhou X, Fang X, Jiang Y, et al. Klotho, an anti-aging gene, acts as a tumor suppressor and inhibitor of IGF-1R signaling in diffuse large B cell lymphoma. J Hematol Oncol. 2017;10(1):37. doi: https://doi.org/10.1186/s13045-017-0391-5Zhou X, Zhang Y, Li Y, et al. Klotho suppresses tumor progression via inhibiting IGF-1R signaling in Tcell lymphoma. Oncol Rep. 2017;38(2):967–974. doi: https://doi.org/10.3892/or.2017.5744Neyra JA, Hu MC. Potential application of klotho in human chronic kidney disease. Bone. 2017;100:41–49. doi: https://doi.org/10.1016/j.bone.2017.01.017Santiago-Ortiz JL, Schaffer DV. Adeno-associated virus (AAV) vectors in cancer gene therapy. J Control Release. 2016;240:287–301. doi: https://doi.org/10.1016/j.jconrel.2016.01.001Kotterman MA, Schaffer DV. Engineering adeno-associated viruses for clinical gene therapy. Nat Rev Genet. 2014;15(7):445–451. doi: https://doi.org/10.1038/nrg3742Davidsohn N, Pezone M, Vernet A, et al. A single combination gene therapy treats multiple age-related diseases. Proc Natl Acad Sci U S A. 2019;116(47):23505–23511. doi: https://doi.org/10.1073/pnas.1910073116Shin YJ, Luo K, Quan Y, et al. Therapeutic challenge of minicircle vector encoding klotho in animal model. Am J Nephrol. 2019;49:413–423. doi: https://doi.org/10.1159/000499863Seo M, Kim MS, Jang A, et al. Epigenetic suppression of the anti-aging gene KLOTHO in human prostate cancer cell lines. Anim Cells Syst (Seoul). 2017;21(4):223–232. doi: https://doi.org/10.1080/19768354.2017.1336112Scourzic L, Mouly E, Bernard OA. TET proteins and the control of cytosine demethylation in cancer. Genome Med. 2015;7(1):9. doi: https://doi.org/10.1186/s13073-015-0134-6Gu Y, Chen J, Zhang H, et al. Hydrogen sulfide attenuates renal fibrosis by inducing TET-dependent DNA demethylation on Klotho promoter. FASEB J. 2020;34(9):11474–11487. doi: https://doi.org/10.1096/fj.201902957RRBauer C, Göbel K, Nagaraj N, et al. Phosphorylation of TET proteins is regulated via O-GlcNAcylation by the O-linked N-acetylglucosamine transferase (OGT). J Biol Chem. 2015 Feb 20;290(8):4801–4812. doi: https://doi.org/10.1074/jbc.M114.605881Taghbalout A, Du M, Jillette N, et al. Enhanced CRISPR-based DNA demethylation by Casilio-ME-mediated RNA-guided coupling of methylcytosine oxidation and DNA repair pathways. Nat Commun. 2019;10(1):4296. doi: https://doi.org/10.1038/s41467-019-12339-7Liu XS, Wu H, Ji X, et al. Editing DNA Methylation in the Mammalian Genome. Cell. 2016;167(1):233–247.e17. doi: https://doi.org/10.1016/j.cell.2016.08.056Xu X, Tao Y, Gao X, et al. A CRISPR-based approach for targeted DNA demethylation. Cell Discov. 2016;2:16009. doi: https://doi.org/10.1038/celldisc.2016.9King GD, Chen C, Huang MM, et al. Identification of novel small molecules that elevate Klotho expression. Biochem J. 2012;441(1):453–461. doi: https://doi.org/10.1042/BJ20101909Hu MC, Shi M, Gillings N, et al. Recombinant α-Klotho may be prophylactic and therapeutic for acute to chronic kidney disease progression and uremic cardiomyopathy. Kidney Int. 2017;91(5):1104–1114. doi: https://doi.org/10.1016/j.kint.2016.10.034Mencke R, Olauson H, Hillebrands JL. Effects of Klotho on fibrosis and cancer: A renal focus on mechanisms and therapeutic strategies. Adv Drug Deliv Rev. 2017;121:85–100. doi: https://doi.org/10.1016/j.addr.2017.07.009Chen B, Zhao H, Li M, et al. SHANK1 facilitates non-small cell lung cancer processes through modulating the ubiquitination of Klotho by interacting with MDM2. Cell Death Dis. 2022;13(4):403. doi: https://doi.org/10.1038/s41419-022-04860-3Usuda J, Ichinose S, Ishizumi T, et al. Klotho is a novel biomarker for good survival in resected large cell neuroendocrine carcinoma of the lung. Lung Cancer. 2011;72(3),355–359. doi: https://doi.org/10.1016/j.lungcan.2010.10.008Dehghani M, Brobey RK, Wang Y, et al. Klotho inhibits EGF-induced cell migration in Caki-1 cells through inactivation of EGFR and p38 MAPK signaling pathways. Oncotarget. 2018;9(42):26737–26750. doi: https://doi.org/10.18632/oncotarget.25481Abolghasemi M, Yousefi T, Maniati M, et al. The interplay of Klotho with signaling pathway and microRNAs in cancers. J Cell Biochem. 2019;120(9):14306–14317. doi: https://doi.org/10.1002/jcb.29022