TESTIN Induces Rapid Death and Suppresses Proliferation in Childhood B Acute Lymphoblastic Leukaemia Cells

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2016 Mar 18

PMID 26985820

Citations 10

Authors

Robert J Weeks

Jackie L Ludgate

Gwenn LeMee

Ian M Morison

Affiliations

Soon will be listed here.

Abstract

Background: Childhood acute lymphoblastic leukaemia (ALL) is the most common malignancy in children. Despite high cure rates, side effects and late consequences of the intensive treatments are common. Unquestionably, the identification of new therapeutic targets will lead to safer, more effective treatments. We identified TES promoter methylation and transcriptional silencing as a very common molecular abnormality in childhood ALL, irrespective of molecular subtype. The aims of the present study were to demonstrate that TES promoter methylation is aberrant, to determine the effects of TES re-expression in ALL, and to determine if those effects are mediated via TP53 activity.

Methods: Normal fetal and adult tissue DNA was isolated and TES promoter methylation determined by Sequenom MassARRAY. Quantitative RT-PCR and immunoblot were used to confirm re-expression of TES in ALL cell lines after 5'-aza-2'-deoxycytidine (decitabine) exposure or transfection with TES expression plasmids. The effects of TES re-expression on ALL cells were investigated using standard cell proliferation, cell death and cell cycle assays.

Results: In this study, we confirm that the TES promoter is unmethylated in normal adult and fetal tissues. We report that decitabine treatment of ALL cell lines results in demethylation of the TES promoter and attendant expression of TES mRNA. Re-expression of TESTIN protein in ALL cells using expression plasmid transfection results in rapid cell death or cell cycle arrest independent of TP53 activity.

Conclusions: These results suggest that TES is aberrantly methylated in ALL and that re-expression of TESTIN has anti-leukaemia effects which point to novel therapeutic opportunities for childhood ALL.

Citing Articles

The value of lung function assessment and Testin expression detection in clinicopathological features and prognosis of NSCLC patients.

Zhang Y, Wang G, Zhang Q, Wang Q, Luo J, Ling C J Cardiothorac Surg. 2024; 19(1):223.

PMID: 38627776 PMC: 11020752. DOI: 10.1186/s13019-024-02720-z.

Study on the expression of testin in the testes of dogs.

Ciaputa R, Nowak M, Dzimira S, Brambilla E, Kandefer-Gola M, Tomaszek A J Vet Res. 2023; 67(4):627-633.

PMID: 38130450 PMC: 10730544. DOI: 10.2478/jvetres-2023-0055.

Silencing of Testin expression is a frequent event in spontaneous lymphomas from Trp53-mutant mice.

Weeks R, Ludgate J, Le Mee G, Khanal R, Mehta S, Williams G Sci Rep. 2020; 10(1):16255.

PMID: 33004921 PMC: 7530732. DOI: 10.1038/s41598-020-73229-3.

A comparative analysis of gene expression induced by the embryo in the caprine endometrium.

Liu X, Zhang L, Han J, Yang L, Cui J, Che S Vet Med Sci. 2019; 6(2):196-203.

PMID: 31782264 PMC: 7196676. DOI: 10.1002/vms3.221.

Testin protects against cardiac hypertrophy by targeting a calcineurin-dependent signalling pathway.

Gao L, Liu Y, Guo S, Xiao L, Liang C, Wang X J Cell Mol Med. 2018; 23(1):328-339.

PMID: 30467953 PMC: 6307772. DOI: 10.1111/jcmm.13934.

References

Stresemann C, Lyko F . Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine. Int J Cancer. 2008; 123(1):8-13. DOI: 10.1002/ijc.23607. View

Zhu J, Li X, Kong X, Moran M, Su P, Haffty B . Testin is a tumor suppressor and prognostic marker in breast cancer. Cancer Sci. 2012; 103(12):2092-101. PMC: 7659249. DOI: 10.1111/cas.12020. View

Zhong Y, Zhu J, Wang Y, Zhou J, Ren K, Ding X . LIM domain protein TES changes its conformational states in different cellular compartments. Mol Cell Biochem. 2008; 320(1-2):85-92. DOI: 10.1007/s11010-008-9901-7. View

Dockerty J . Epidemiology of childhood leukemia in New Zealand: studies of infectious hypotheses. Blood Cells Mol Dis. 2008; 42(2):113-6. DOI: 10.1016/j.bcmd.2008.10.008. View

Gunduz E, Gunduz M, Beder L, Nagatsuka H, Fukushima K, Sutcu R . Downregulation of TESTIN and its association with cancer history and a tendency toward poor survival in head and neck squamous cell carcinoma. Arch Otolaryngol Head Neck Surg. 2009; 135(3):254-60. DOI: 10.1001/archoto.2008.560. View

Martin-Subero J, Ammerpohl O, Bibikova M, Wickham-Garcia E, Agirre X, Alvarez S . A comprehensive microarray-based DNA methylation study of 367 hematological neoplasms. PLoS One. 2009; 4(9):e6986. PMC: 2737286. DOI: 10.1371/journal.pone.0006986. View

Schultz K, Bowman W, Aledo A, Slayton W, Sather H, Devidas M . Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a children's oncology group study. J Clin Oncol. 2009; 27(31):5175-81. PMC: 2773475. DOI: 10.1200/JCO.2008.21.2514. View

Qiu H, Zhu J, Yuan C, Yan S, Yang Q, Kong B . Frequent hypermethylation and loss of heterozygosity of the testis derived transcript gene in ovarian cancer. Cancer Sci. 2010; 101(5):1255-60. PMC: 11159749. DOI: 10.1111/j.1349-7006.2010.01497.x. View

Weeks R, Kees U, Song S, Morison I . Silencing of TESTIN by dense biallelic promoter methylation is the most common molecular event in childhood acute lymphoblastic leukaemia. Mol Cancer. 2010; 9:163. PMC: 3224738. DOI: 10.1186/1476-4598-9-163. View

10.

Ma H, Weng D, Chen Y, Huang W, Pan K, Wang H . Extensive analysis of D7S486 in primary gastric cancer supports TESTIN as a candidate tumor suppressor gene. Mol Cancer. 2010; 9:190. PMC: 2915979. DOI: 10.1186/1476-4598-9-190. View

11.

Fujiwara T, Lee H, Sanalkumar R, Bresnick E . Building multifunctionality into a complex containing master regulators of hematopoiesis. Proc Natl Acad Sci U S A. 2010; 107(47):20429-34. PMC: 2996669. DOI: 10.1073/pnas.1007804107. View

12.

Novershtern N, Subramanian A, Lawton L, Mak R, Nicholas Haining W, McConkey M . Densely interconnected transcriptional circuits control cell states in human hematopoiesis. Cell. 2011; 144(2):296-309. PMC: 3049864. DOI: 10.1016/j.cell.2011.01.004. View

13.

Crone J, Glas C, Schultheiss K, Moehlenbrink J, Krieghoff-Henning E, Hofmann T . Zyxin is a critical regulator of the apoptotic HIPK2-p53 signaling axis. Cancer Res. 2011; 71(6):2350-9. DOI: 10.1158/0008-5472.CAN-10-3486. View

14.

Boeda B, Knowles P, Briggs D, Murray-Rust J, Soriano E, Garvalov B . Molecular recognition of the Tes LIM2-3 domains by the actin-related protein Arp7A. J Biol Chem. 2011; 286(13):11543-54. PMC: 3064208. DOI: 10.1074/jbc.M110.171264. View

15.

Tatarelli C, Linnenbach A, Mimori K, Croce C . Characterization of the human TESTIN gene localized in the FRA7G region at 7q31.2. Genomics. 2000; 68(1):1-12. DOI: 10.1006/geno.2000.6272. View

16.

Mori H, Colman S, Xiao Z, Ford A, Healy L, Donaldson C . Chromosome translocations and covert leukemic clones are generated during normal fetal development. Proc Natl Acad Sci U S A. 2002; 99(12):8242-7. PMC: 123052. DOI: 10.1073/pnas.112218799. View

17.

Garvalov B, Higgins T, Sutherland J, Zettl M, Scaplehorn N, Kocher T . The conformational state of Tes regulates its zyxin-dependent recruitment to focal adhesions. J Cell Biol. 2003; 161(1):33-9. PMC: 2172870. DOI: 10.1083/jcb.200211015. View

18.

Matthews J, Lester K, Joseph S, Curtis D . LIM-domain-only proteins in cancer. Nat Rev Cancer. 2013; 13(2):111-22. DOI: 10.1038/nrc3418. View

19.

Skiriute D, Vaitkiene P, Asmoniene V, Steponaitis G, Deltuva V, Tamasauskas A . Promoter methylation of AREG, HOXA11, hMLH1, NDRG2, NPTX2 and Tes genes in glioblastoma. J Neurooncol. 2013; 113(3):441-9. DOI: 10.1007/s11060-013-1133-3. View

20.

Gu Z, Ding G, Liang K, Zhang H, Guo G, Zhang L . TESTIN suppresses tumor growth and invasion via manipulating cell cycle progression in endometrial carcinoma. Med Sci Monit. 2014; 20:980-7. PMC: 4067424. DOI: 10.12659/MSM.890544. View