Changes in expression of klotho affect physiological processes, diseases, and cancer

Document Type: Review Article

Authors

Institute of Genome Research, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet, Cau Giay, Hanoi, Vietnam

Abstract

Klotho (KL) encodes a single-pass transmembrane protein and is predominantly expressed in the kidney, parathyroid glands, and choroid plexus. Genetic studies on the KL gene have revealed that DNA hypermethylation is one of the major risk factors for aging, diseases, and cancer. Besides, KL exerts anti-inflammatory and anti-tumor effects by regulating signaling pathways and the expression of target genes. KL participates in modulation of the insulin/insulin-like growth factor-1 (IGF-1) signaling, which induces the growth hormone (GH) secretion. Accordingly, KL mutant mice display multiple aging-like phenotypes, which are ameliorated by overexpression of KL. Therefore, KL is an important contributor to lifespan. KL is further identified as a regulator of calcium (Ca2+) channel-dependent cell physiological processes. KL has been also shown to induce cancer cell apoptosis, thus, it is considered as a potential tumor suppressor. Our recent studies have indicated that KL modulates an influx of Ca2+ from the extracellular space, leading to a change in CCL21-dependent migration in dendritic cells (DCs). Interestingly, the regulation of the expression of KL was mediated through a phosphoinositide 3-kinase (PI3K) pathway in DCs. Moreover, downregulating of KL expression by using siRNA knockdown technique, we observed that the expression of Ca2+ channels including Orai3, but not Orai1, Orai2, TRPV5 and TRPV6 was significantly reduced in KL-silenced as compared to control BMDCs. Clearly, additional research is required to define the role of KL in the regulation of organismic and cellular functions through the PI3K signaling and the expression of the Ca2+ channels.

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1. Sopjani M, Dermaku-Sopjani M. Klotho-dependent cellular transport regulation. Vitam Horm 2016; 101: 59-84.

2. Kuro-o M. Klotho and aging. Biochim Biophys Acta 2009; 1790: 1049-1058.

3. Cha SK, Ortega B, Kurosu H, Rosenblatt KP, Kuro OM, Huang CL. Removal of sialic acid involving klotho causes cell-surface retention of TRPV5 channel via binding to galectin-1. Proc Natl Acad Sci U S A 2008; 105: 9805-9810.

4. Xuan NT, Hoang NH, Nhung VP, Duong NT, Ha NH, Hai NV. Regulation of dendritic cell function by insulin/IGF-1/PI3K/Akt signaling through klotho expression. J Recept Signal Transduct Res 2016; 37: 1-7.

5. Kurosu H, Yamamoto M, Clark JD, Pastor JV, Nandi A, Gurnani P, et al. Suppression of aging in mice by the hormone Klotho. Science 2005; 309: 1829-1833.

6. Rubinek T, Modan-Moses D. Klotho and the growth hormone/insulin-like growth factor 1 axis: novel insights into complex interactions. Vitam Horm 2016; 101: 85-118.

7. Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 1997; 390: 45-51.

8. Liu Y, Zhang Q. Periodontitis aggravated pancreatic beta-cell dysfunction in diabetic mice through interleukin-12 regulation on Klotho. J Diabetes Investig 2016; 7: 303-311.

9. Okada S, Yoshida T, Hong Z, Ishii G, Hatano M, Kuro OM, et al. Impairment of B lymphopoiesis in precocious aging (klotho) mice. Int Immunol 2000; 12: 861-871.

10. Chen CD, Sloane JA, Li H, Aytan N, Giannaris EL, Zeldich E, et al. The antiaging protein klotho enhances oligodendrocyte maturation and myelination of the CNS. J Neurosci 2013; 33: 1927-1939.

11. Liu H, Fergusson MM, Castilho RM, Liu J, Cao L, Chen J, et al. Augmented Wnt signaling in a mammalian model of accelerated aging. Science 2007; 317: 803-806.

12. Carracedo J, Buendia P, Merino A, Madueno JA, Peralbo E, Ortiz A, et al. Klotho modulates the stress response in human senescent endothelial cells. Mech Ageing Dev 2012; 133: 647-654.

13. Wang Y, Kuro-o M, Sun Z. Klotho gene delivery suppresses Nox2 expression and attenuates oxidative stress in rat aortic smooth muscle cells via the cAMP-PKA pathway. Aging Cell 2012; 11: 410-417.

14. de Oliveira RM. Klotho RNAi induces premature senescence of human cells via a p53/p21 dependent pathway. FEBS Lett 2006; 580: 5753-5758.

15. Kokkinaki M, Abu-Asab M, Gunawardena N, Ahern G, Javidnia M, Young J, et al. Klotho regulates retinal pigment epithelial functions and protects against oxidative stress. J Neurosci 2013; 33: 16346-1659.

16. Markiewicz M, Panneerselvam K, Marks N. Role of Klotho in migration and proliferation of human dermal microvascular endothelial cells. Microvasc Res 2016; 107: 76-82.

17. Liu CY, Zhang ZH, Yang HF, Xu H, Cheng FF, Xu JZ. Effect of vitamin D3 on maturation and antigen-presenting function of dendritic cells treated with Mycobacterium tuberculosis. Asian Pac J Trop Med 2016; 9: 54-57.

18. Shumilina E, Nurbaeva MK, Yang W, Schmid E, Szteyn K, Russo A, et al. Altered regulation of cytosolic Ca(2)(+) concentration in dendritic cells from klotho hypomorphic mice. Am J Physiol Cell Physiol 2013; 305: C70-77.

19. Leibrock CB, Voelkl J, Kuro OM, Lang F, Lang UE. 1,25(OH)2D3 dependent overt hyperactivity phenotype in klotho-hypomorphic mice. Sci Rep 2016; 6: 24879.

20. Matzner N, Zemtsova IM, Nguyen TX, Duszenko M, Shumilina E, Lang F. Ion channels modulating mouse dendritic cell functions. J Immunol 2008; 181: 6803-6809.

21. Zhou X, Yang W, Li J. Ca2+- and protein kinase C-dependent signaling pathway for nuclear factor-kappaB activation, inducible nitric-oxide synthase expression, and tumor necrosis factor-alpha production in lipopolysaccharide-stimulated rat peritoneal macrophages. J Biol Chem 2006; 281: 31337-31347.

22. Borst O, Munzer P, Schmid E, Schmidt EM, Russo A, Walker B, et al. 1,25(OH)2 vitamin D3-dependent inhibition of platelet Ca2+ signaling and thrombus formation in klotho-deficient mice. FASEB J 2014; 28: 2108-2119.

23. Zhang B, Yan J, Umbach AT, Fakhri H, Fajol A, Schmidt S, et al. NFkappaB-sensitive Orai1 expression in the regulation of FGF23 release. J Mol Med (Berl) 2016; 94: 557-566.

24. Luik RM, Wang B, Prakriya M, Wu MM, Lewis RS. Oligomerization of STIM1 couples ER calcium depletion to CRAC channel activation. Nature 2008; 454: 538-542.

25. Schoeber JP, Hoenderop JG, Bindels RJ. Concerted action of associated proteins in the regulation of TRPV5 and TRPV6. Biochem Soc Trans 2007; 35: 115-119.

26. Topala CN, Bindels RJ, Hoenderop JG. Regulation of the epithelial calcium channel TRPV5 by extracellular factors. Curr Opin Nephrol Hypertens 2007; 16: 319-324.

27. Lee J, Jeong DJ, Kim J, Lee S, Park JH, Chang B, et al. The anti-aging gene KLOTHO is a novel target for epigenetic silencing in human cervical carcinoma. Mol Cancer 2010; 9: 109.

28. Shu G, Xie B, Ren F, Liu DC, Zhou J, Li Q, et al. Restoration of klotho expression induces apoptosis and autophagy in hepatocellular carcinoma cells. Cell Oncol (Dordr) 2013; 36: 121-129.

29. Sun CY, Chang SC, Wu MS. Suppression of Klotho expression by protein-bound uremic toxins is associated with increased DNA methyltransferase expression and DNA hypermethylation. Kidney Int 2012; 81: 640-650.

30. Yamazaki Y, Imura A, Urakawa I, Shimada T, Murakami J, Aono Y, et al. Establishment of sandwich ELISA for soluble alpha-Klotho measurement: Age-dependent change of soluble alpha-Klotho levels in healthy subjects. Biochem Biophys Res Commun 2010; 398: 513-518.

31. Yamagishi T, Saito Y, Nakamura T, Takeda S, Kanai H, Sumino H, et al. Troglitazone improves endothelial function and augments renal klotho mRNA expression in Otsuka Long-Evans Tokushima Fatty (OLETF) rats with multiple atherogenic risk factors. Hypertens Res 2001; 24: 705-709.

32. Hsu SC, Huang SM, Lin SH, Ka SM, Chen A, Shih MF, et al. Testosterone increases renal anti-aging klotho gene expression via the androgen receptor-mediated pathway. Biochem J 2014; 464: 221-229.

33. Oz OK, Hajibeigi A, Howard K, Cummins CL, van Abel M, Bindels RJ, et al. Aromatase deficiency causes altered expression of molecules critical for calcium reabsorption in the kidneys of female mice *. J Bone Miner Res 2007; 22: 1893-1902.

34. Xuan NT, Trang PT, Van Phong N, Toan NL, Trung DM, Bac ND, et al. Klotho sensitive regulation of dendritic cell functions by vitamin E. Biol Res 2016; 49: 45.

35. Nagai T, Yamada K, Kim HC, Noda Y, Nabeshima Y, Nabeshima T. [Cognition impairment in the klotho gene mutant mice and oxidative stress]. Nihon Shinkei Seishin Yakurigaku Zasshi 2003; 23: 211-217.

36. Kawamura Y, Matsuo H, Chiba T, Nagamori S, Nakayama A, Inoue H, et al. Pathogenic GLUT9 mutations causing renal hypouricemia type 2 (RHUC2). Nucleosides Nucleotides Nucleic Acids 2011; 30: 1105-1111.

37. Vadakke Madathil S, Coe LM, Casu C, Sitara D. Klotho deficiency disrupts hematopoietic stem cell development and erythropoiesis. Am J Pathol 2014; 184: 827-841.

38. Dinour D, Bahn A, Ganon L, Ron R, Geifman-Holtzman O, Knecht A, et al. URAT1 mutations cause renal hypouricemia type 1 in Iraqi Jews. Nephrol Dial Transplant 2011; 26: 2175-2181.

39. Doege H, Bocianski A, Joost HG, Schurmann A. Activity and genomic organization of human glucose transporter 9 (GLUT9), a novel member of the family of sugar-transport facilitators predominantly expressed in brain and leucocytes. Biochem J 2000; 350 Pt 3: 771-776.

40. Koh N, Fujimori T, Nishiguchi S, Tamori A, Shiomi S, Nakatani T, et al. Severely reduced production of klotho in human chronic renal failure kidney. Biochem Biophys Res Commun 2001; 280: 1015-1020.

41. Semba RD, Cappola AR, Sun K, Bandinelli S, Dalal M, Crasto C, et al. Plasma klotho and cardiovascular disease in adults. J Am Geriatr Soc 2011; 59: 1596-1601.

42. Karalliedde J, Maltese G, Hill B, Viberti G, Gnudi L. Effect of renin-angiotensin system blockade on soluble Klotho in patients with type 2 diabetes, systolic hypertension, and albuminuria. Clin J Am Soc Nephrol 2013; 8: 1899-1905.

43. Schmid C, Neidert MC, Tschopp O, Sze L, Bernays RL. Growth hormone and Klotho. J Endocrinol 2013; 219: R37-57.

44. Wang L, Wang X, Jie P, Lu H, Zhang S, Lin X, et al. Klotho is silenced through promoter hypermethylation in gastric cancer. Am J Cancer Res 2011; 1: 111-119.

45. Rubinek T, Shulman M, Israeli S, Bose S, Avraham A, Zundelevich A, et al. Epigenetic silencing of the tumor suppressor klotho in human breast cancer. Breast Cancer Res Treat 2012; 133: 649-657.

46. Pan J, Zhong J, Gan LH, Chen SJ, Jin HC, Wang X, et al. Klotho, an anti-senescence related gene, is frequently inactivated through promoter hypermethylation in colorectal cancer. Tumour Biol 2011; 32: 729-735.

47. Wolf I, Levanon-Cohen S, Bose S, Ligumsky H, Sredni B, Kanety H, et al. Klotho: a tumor suppressor and a modulator of the IGF-1 and FGF pathways in human breast cancer. Oncogene 2008; 27: 7094-7105.

48. MacDonald BT, Tamai K, He X. Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell 2009; 17: 9-26.

49. Shimoyama Y, Taki K, Mitsuda Y, Tsuruta Y, Hamajima N, Niwa T. KLOTHO gene polymorphisms G-395A and C1818T are associated with low-density lipoprotein cholesterol and uric acid in Japanese hemodialysis patients. Am J Nephrol 2009; 30: 383-388.

50. Pollak MN, Schernhammer ES, Hankinson SE. Insulin-like growth factors and neoplasia. Nat Rev Cancer 2004; 4: 505-518.

51. Lojkin I, Rubinek T, Orsulic S, Schwarzmann O, Karlan BY, Bose S,et al. Reduced expression and growth inhibitory activity of the aging suppressor klotho in epithelial ovarian cancer. Cancer Lett 2015; 362: 149-157.

52. Lorenzi O, Veyrat-Durebex C, Wollheim CB, Villemin P, Rohner-Jeanrenaud F, Zanchi A, et al. Evidence against a direct role of klotho in insulin resistance. Pflugers Arch 2010; 459: 465-473.

53. Giles RH, van Es JH, Clevers H. Caught up in a Wnt storm: Wnt signaling in cancer. Biochim Biophys Acta 2003; 1653: 1-24.

54. Chen B, Wang X, Zhao W, Wu J. Klotho inhibits growth and promotes apoptosis in human lung cancer cell line A549. J Exp Clin Cancer Res 2010; 29: 99.

55. Wolf I, Laitman Y, Rubinek T, Abramovitz L, Novikov I, Beeri R, et al. Functional variant of KLOTHO: a breast cancer risk modifier among BRCA1 mutation carriers of Ashkenazi origin. Oncogene 2010; 29: 26-33.

56. Arking DE, Krebsova A, Macek M, Sr., Macek M, Jr., Arking A, Mian IS, et al. Association of human aging with a functional variant of klotho. Proc Natl Acad Sci U S A 2002; 99: 856-861.

57. Arking DE, Atzmon G, Arking A, Barzilai N, Dietz HC. Association between a functional variant of the KLOTHO gene and high-density lipoprotein cholesterol, blood pressure, stroke, and longevity. Circ Res 2005; 96: 412-418.

58. Rhee EJ, Oh KW, Yun EJ, Jung CH, Lee WY, Kim SW, et al. Relationship between polymorphisms G395A in promoter and C1818T in exon 4 of the KLOTHO gene with glucose metabolism and cardiovascular risk factors in Korean women. J Endocrinol Invest 2006; 29: 613-618.

59. Liu C, Cui W, Wang L, Yan L, Ruan X, Liu Y, et al. Klotho gene polymorphisms are related to colorectal cancer susceptibility. Int J Clin Exp Pathol 2015; 8: 7446-7449.

60. Wang HL, Xu Q, Wang Z, Zhang YH, Si LY, Li XJ, et al. A potential regulatory single nucleotide polymorphism in the promoter of the Klotho gene may be associated with essential hypertension in the Chinese Han population. Clin Chim Acta 2010; 411: 386-390.

61. Rhee EJ, Oh KW, Lee WY, Kim SY, Jung CH, Kim BJ, et al. The differential effects of age on the association of KLOTHO gene polymorphisms with coronary artery disease. Metabolism 2006; 55: 1344-1351.

62. Nolan VG, Baldwin C, Ma Q, Wyszynski DF, Amirault Y, Farrell JJ, et al. Association of single nucleotide polymorphisms in klotho with priapism in sickle cell anaemia. Br J Haematol 2005; 128: 266-272.

63. Lustosa Souza CR, Azevedo Shimmoto MM, Vicari P, Mecabo G, Arruda MM, Figueiredo MS. Klotho gene polymorphisms and their association with sickle cell disease phenotypes. Rev Bras Hematol Hemoter 2015; 37: 275-276.

64. Friedman DJ, Afkarian M, Tamez H, Bhan I, Isakova T, Wolf M, et al. Klotho variants and chronic hemodialysis mortality. J Bone Miner Res 2009; 24: 1847-1855.