PDLIM2 and Its Role in Oncogenesis – Tumor Suppressor or Oncoprote?

Česká verzia

Authors: J. Maryáš ¹; P. Bouchal ^1,2
Authors place of work: Regionální centrum aplikované molekulární onkologie, Masarykův onkologický ústav, Brno2 Ústav biochemie, PřF MU, Brno ¹
Published in the journal: Klin Onkol 2015; 28(Supplementum 2): 40-46
doi: https://doi.org/10.14735/amko20152S40

Summary

PDZ and LIM domain containing protein 2 (PDLIM2), also known as Mystique or SLIM, is a member of the actinin – associated LIM family of proteins that play essential roles in cytoskeletone organization, cell differentiation and have been associated with oncogenesis. PDLIM2 is cytoskeletal and nuclear protein encoded by the Mystique gene localized on chromosome 8p21. PDLIM2 regulates stability and activity of several transcription factors, e. g. NF κB or STAT, and its deregulation is associated with several malignancies. PDLIM2 expression has been connected with both tumor suppression and tumorigenesis. PDLIM2 levels are epigenetically suppressed in different cancers due to Mystique promoter hypermetylation that blocks its transcription. PDLIM2 re expression is able to inhibit tumorigenicity and induces tumor cell death both in vitro and in vivo, which suggest potential tumor suppressor role of PDLIM2. On the other hand, PDLIM2 is highly expressed in cancer cell lines derived from metastatic cancer and its expression is associated with tumor progression and metastasis formation, indicating pro oncogenic role of PDLIM2. The aim of this review is to summarize current knowledge on the role of PDLIM2 in tumor formation and development, focusing on its prospective role as therapeutic target and offering potential explanations of its different functions in oncogenesis that were identified so far.

Key words:
PDLIM2 protein – COP9 signalosome (CSN) – oncogenesis – 5- aza- 2’- deoxycytidine – cancer – metastasis

This study was supported by Czech Science Foundation (project No. 14-19250S), European Regional Development Fund and the State Budget of the Czech Republic (OP VaVpI – RECAMO CZ.1.05/2.1.00/03.0101), Brno Ph.D. Talent Scholarship programme – Funded by the Brno City Municipality, by the project MEYS – NPS I – LO1413, MH CZ – DRO (MMCI, 00209805) and BBMRI_CZ (LM2010004).

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE “uniform requirements” for biomedical papers.

Submitted:
27. 3. 2015

Accepted:
29. 6. 2015

Zdroje

1. Healy NC, O‘Connor R. Sequestration of PDLIM2 in the cytoplasm of monocytic/ macrophage cells is associated with adhesion and increased nuclear activity of NF‑ kappaB. J Leukoc Biol 2009; 85(3): 481– 490. doi: 10.1189/ jlb.0408238.

2. Torrado M, Senatorov VV, Trivedi R et al. Pdlim2, a novel PDZ‑ LIM domain protein, interacts with alpha‑ actinins and filamin A. Invest Ophthalmol Vis Sci 2004; 45(11): 3955– 3963.

3. Loughran G, Healy NC, Kiely PA et al. Mystique is a new insulin‑like growth factor‑ I‑ regulated PDZ‑ LIM domain protein that promotes cell attachment and migration and suppresses Anchorage‑ independent growth. Mol Biol Cell 2005; 16(4): 1811– 1822.

4. Qu Z, Yan P, Fu J et al. DNA methylation‑ dependent repression of PDZ‑ LIM domain‑containing protein 2 in colon cancer and its role as a potential therapeutic target. Cancer Res 2010; 70(5): 1766– 1772. doi: 10.1158/ 0008‑ 5472.CAN‑ 09‑ 3263.

5. te Velthuis AJ, Bagowski CP. PDZ and LIM domain‑encoding genes: molecular interactions and their role in development. Scientific World Journal 2007; 7: 1470– 1492.

6. Deevi RK, Cox OT, O‘Connor R. Essential function for PDLIM2 in cell polarization in three‑ dimensional cultures by feedback regulation of the β1- integrin‑RhoA signaling axis. Neoplasia 2014; 16(5): 422– 431. doi: 10.1016/ j.neo.2014.04.006.

7. Bowe RA, Cox OT, Ayllón V et al. PDLIM2 regulates transcription factor activity in epithelial‑ to‑ mesenchymal transition via the COP9 signalosome. Mol Biol Cell 2014; 25(1): 184– 195. doi: 10.1091/ mbc.E13‑ 06‑ 0306.

8. Macartney‑ Coxson DP, Hood KA, Shi HJ et al. Metastatic susceptibility locus, an 8p hot‑ spot for tumour progression disrupted in colorectal liver metastases: 13 candidate genes examined at the DNA, mRNA and protein level. BMC Cancer 2008; 8: 187. doi: 10.1186/ 1471‑ 2407‑ 8‑ 187.

9. Zhao T, Yasunaga J, Satou Y et al. Human T‑ cell leukemia virus type 1 bZIP factor selectively suppresses the classical pathway of NF‑ kappaB. Blood 2009; 113(12): 2755– 2764. doi: 10.1182/ blood‑ 2008‑ 06‑ 161729.

10. Yan P, Qu Z, Ishikawa C et al. Human T‑ cell leukemia virus type I‑ mediated repression of PDZ‑ LIM domain‑containing protein 2 involves DNA methylation but independent of the viral oncoprotein tax. Neoplasia 2009; 11(10): 1036– 1041.

11. Fu J, Yan P, Li S et al. Molecular determinants of PDLIM2 in suppressing HTLV‑ I Tax‑ mediated tumorigenesis. Oncogene 2010; 29(49): 6499– 6507. doi: 10.1038/ onc.2010.374.

12. Yan P, Fu J, Qu Z et al. PDLIM2 suppresses human T‑ cell leukemia virus type I Tax‑ mediated tumorigenesis by targeting Tax into the nuclear matrix for proteasomal degradation. Blood 2009; 113(18): 4370– 4380. doi: 10.1182/ blood‑ 2008‑ 10‑ 185660.

13. Liu S, Sun X, Wang M et al. A microRNA 221- and 222- mediated feedback loop maintains constitutive activation of NFκB and STAT3 in colorectal cancer cells. Gastroenterology 2014; 147(4): 847– 859. doi: 10.1053/ j.gastro.2014.06.006.

14. Qu Z, Fu J, Yan P et al. Epigenetic repression of PDZ‑ LIM domain‑containing protein 2: implications for the biology and treatment of breast cancer. J Biol Chem 2010; 285(16): 11786– 11792. doi: 10.1074/ jbc.M109.086561.

15. Vanoirbeek E, Eelen G, Verlinden L et al. PDLIM2 expression is driven by vitamin D and is involved in the pro‑adhesion, and anti‑migration and - invasion activity of vitamin D. Oncogene 2014; 33(15): 1904– 1911. doi: 10.1038/ onc.2013.123.

16. Basak S, Kim H, Kearns JD et al. A fourth IkappaB protein within the NF‑ kappaB signaling module. Cell 2007; 128(2): 369– 381.

17. Hayden MS, Ghosh S et al. Shared principles in NF‑ kappaB signaling. Cell 2008; 132(3): 344– 362. doi: 10.1016/ j.cell.2008.01.020.

18. Pikarsky E, Porat RM, Stein I et al. NF‑ kappaB functions as a tumour promoter in inflammation‑associated cancer. Nature 2004; 431(7007): 461– 466.

19. Yamaoka S, Inoue H, Sakurai M et al. Constitutive activation of NF‑ kappa B is essential for transformation of rat fibroblasts by the human T‑ cell leukemia virus type I Tax protein. EMBO J 1996; 15(4): 873– 887.

20. Higuchi M, Tsubata C, Kondo R et al. Cooperation of NF‑ kappaB2/ p100 activation and the PDZ domain binding motif signal in human T‑ cell leukemia virus type 1 (HTLV‑ 1) Tax1 but not HTLV‑ 2 Tax2 is crucial for interleukin‑2- independent growth transformation. of a T‑ cell line. J Virol 2007; 81(21): 11900– 11907.

21. Keats JJ, Fonseca R, Chesi M et al. Promiscuous mutations activate the noncanonical NF‑ kappaB pathway in multiple myeloma. Cancer Cell 2007; 12(2): 131– 144.

22. Jabbour E, Issa JP, Garcia‑ Manero G et al. Evolution of decitabine development: accomplishments, ongoing investigations, and future strategies. Cancer 2008; 112(11): 2341– 2351. doi: 10.1002/ cncr.23463.

23. Qu Z, Fu J, Ma H et al. PDLIM2 restricts Th1 and Th17 differentiation and prevents autoimmune disease. Cell Biosci 2012; 2(1): 23. doi: 10.1186/ 2045‑ 3701‑ 2‑ 23.

24. Guo H, Mi Z, Bowles DE et al. Osteopontin and protein kinase C regulate PDLIM2 activation and STAT1 ubiquitination in LPS‑treated murine macrophages. J Biol Chem 2010; 285(48): 37787– 37796. doi: 10.1074/ jbc.M110.161869.

25. Biswas DK, Shi Q, Baily S et al. NF‑ kappa B activation in human breast cancer specimens and its role in cell proliferation and apoptosis. Proc Natl Acad Sci U S A 2004; 101(27): 10137– 10142.

26. Lopes N, Sousa B, Martins D et al. Alterations in vitamin D signalling and metabolic pathways in breast cancer progression: a study of VDR, CYP27B1 and CYP24A1 expression in benign and malignant breast lesions. BMC Cancer 2010; 10: 483. doi: 10.1186/ 1471‑ 2407‑ 10‑483.

27. Nieto MA. Epithelial‑ Mesenchymal Transitions in development and disease: old views and new perspectives. Int J Dev Biol 2009; 53(8– 10): 1541– 1547. doi: 10.1387/ ijdb.072410mn.

28. Lee MH, Zhao R, Phan L et al. Roles of COP9 signalosome in cancer. CelL Cycle 2011; 10(18): 3057– 3066.

29. Adler AS, Littlepage LE, Lin M et al. CSN5 isopeptidase activity links COP9 signalosome activation to breast cancer progression. Cancer Res 2008; 68(2): 506– 515. doi: 10.1158/ 0008‑ 5472.CAN‑ 07‑ 3060.

30. Shackleford TJ, Claret FX. JAB1/ CSN5: a new player in cell cycle control and cancer. Cell Div 2010; 5(26). doi: 10.1186/ 1747‑ 1028‑ 5‑ 26.

31. Lisse TS, Hewison M, Adams JS. Hormone response element binding proteins: novel regulators of vitamin D and estrogen signaling. Steroids 2011; 76(4): 331– 339. doi: 10.1016/ j.steroids.2011.01.002.