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Cyclin A1 is a transcriptional target of PITX2 and overexpressed in papillary thyroid carcinoma

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Abstract

Physiological expression of cyclin A1, a unique cell cycle regulator essential for spermatogenesis, is predominantly restricted in male germ cells. Outstandingly, previous studies have also demonstrated the abnormal expression of cyclin A1 in various human tumors. How male germ cell-specific cyclin A1 is transcriptionally activated in tumor cells, however, is elusive. To begin to understand the molecular mechanisms governing the ectopic expression of cyclin A1, we searched for transcription factors and cis-regulatory DNA elements. We found that overexpression of PITX2, a paired-like homeodomain transcription factor and a downstream effector of Wnt/β-catenin signaling, resulted in upregulation of cyclin A1 in HEK293 cells and TPC-1 thyroid cancer cells. On the other hand, PITX2 knockdown in TPC-1 cells caused reduced cyclin A1. Promoter reporter assays with a series of deletion constructs determined that the DNA element from −102 to −96 bp of the cyclin A1 promoter is responsible for PITX2-induced gene expression. The result of chromatin immunoprecipitation revealed the occupancy of PITX2 on the cyclin A1 promoter. Taken together, these findings demonstrate that cyclin A1 is a transcriptional target of PITX2. Consistently, our immunohistochemistry result showed up-regulation of cyclin A1 in human papillary thyroid carcinoma, where overexpressed PITX2 has been endorsed in our recent report. Thus, our study provides new evidence on the regulation of cyclin A1 gene expression and offers a PITX2-cycin A1 pathway for cell cycle regulation.

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References

  1. Murray AW (2004) Recycling the cell cycle: cyclins revisited. Cell 116:221–234

    Article  PubMed  CAS  Google Scholar 

  2. Hochegger H, Takeda S, Hunt T (2008) Cyclin-dependent kinases and cell-cycle transitions: does one fit all? Nat Rev Mol Cell Biol 9:910–916

    Article  PubMed  CAS  Google Scholar 

  3. Yam CH, Fung TK, Poon RY (2002) Cyclin A in cell cycle control and cancer. Cell Mol Life Sci 59:1317–1326

    Article  PubMed  CAS  Google Scholar 

  4. Joshi AR, Jobanputra V, Lele KM, Wolgemuth DJ (2009) Distinct properties of cyclin-dependent kinase complexes containing cyclin A1 and cyclin A2. Biochem Biophys Res Commun 378:595–599

    Article  PubMed  CAS  Google Scholar 

  5. Liu D, Matzuk MM, Sung WK, Guo Q, Wang P et al (1998) Cyclin A1 is required for meiosis in the male mouse. Nat Genet 20:377–380

    Article  PubMed  CAS  Google Scholar 

  6. Panigrahi SK, Vasileva A, Wolgemuth DJ (2012) Sp1 transcription factor and GATA1 cis-acting elements modulate testis-specific expression of mouse cyclin A1. PLoS ONE 7(10):e47862

    Article  PubMed  CAS  Google Scholar 

  7. Yang R, Nakamaki T, Lübbert M, Said J, Sakashita A et al (1999) Cyclin A1 expression in leukemia and normal hematopoietic cells. Blood 93:2067–2074

    PubMed  CAS  Google Scholar 

  8. Coletta RD, Christensen K, Reichenberger KJ, Lamb J, Micomonaco D et al (2004) The Six1 homeoprotein stimulates tumorigenesis by reactivation of cyclin A1. Proc Natl Acad Sci U S A 101:6478–6483

    Article  PubMed  CAS  Google Scholar 

  9. Wegiel B, Bjartell A, Tuomela J, Dizeyi N, Tinzl M et al (2008) Multiple cellular mechanisms related to cyclin A1 in prostate cancer invasion and metastasis. J Natl Cancer Inst 100:1022–1036

    Article  PubMed  CAS  Google Scholar 

  10. Huang Y, Huang K, Boskovic G, Dementieva Y, Denvir J et al (2009) Proteomic and genomic analysis of PITX2 interacting and regulating networks. FEBS Lett 583:638–642

    Article  PubMed  CAS  Google Scholar 

  11. Kioussi C, Briata P, Baek SH, Rose DW, Hamblet NS et al (2002) Identification of a Wnt/Dvl/[beta]-Catenin – > Pitx2 pathway mediating cell-type-specific proliferation during development. Cell 111:673–685

    Article  PubMed  CAS  Google Scholar 

  12. Gage PJ, Suh H, Camper SA (1999) Dosage requirement of Pitx2 for development of multiple organs. Development 126:4643–4651

    PubMed  CAS  Google Scholar 

  13. Lu MF, Pressman C, Dyer R, Johnson RL, Martin JF (1999) Function of Rieger syndrome gene in left-right asymmetry and craniofacial development. Nature 401:276–278

    Article  PubMed  CAS  Google Scholar 

  14. Bamforth SDBJ, Farthing CR, Schneider JE, Broadbent C, Michell AC et al (2004) Cited2 control left-right patterning and heart development through a Nodal-Pitx2c pathway. Nat Genet 36:1189–1196

    Article  PubMed  CAS  Google Scholar 

  15. Ai D, Wang J, Amen M, Lu M-F, Amendt BA et al (2007) Nuclear factor 1 and T-Cell factor/LEF recognition elements regulate Pitx2 transcription in pituitary development. Mol Cell Biol 27:5765–5775

    Article  PubMed  CAS  Google Scholar 

  16. Lin CR, Kioussi C, O’Connell S, Briata P, Szeto D et al (1999) Pitx2 regulates lung asymmetry, cardiac positioning and pituitary and tooth morphogenesis. Nature 401:279–282

    Article  PubMed  CAS  Google Scholar 

  17. Liu C, Liu W, Palie J, Lu MF, Brown NA et al (2002) Pitx2c patterns anterior myocardium and aortic arch vessels and is required for local cell movement into atrioventricular cushions. Development 129:5081–5091

    Article  PubMed  CAS  Google Scholar 

  18. Semina EV, Reiter RS, Murray JC (1997) Isolation of a new homeobox gene belonging to the Pitx/Rieg family: expression during lens development and mapping to the aphakia region on mouse chromosome 19. Hum Mol Genet 6:2109–2116

    Article  PubMed  CAS  Google Scholar 

  19. Lines MA, Kozlowski K, Walter MA (2002) Molecular genetics of Axenfeld-Rieger malformations. Hum Mol Genet 11:1177–1187

    Article  PubMed  CAS  Google Scholar 

  20. Espinoza HM, Cox CJ, Semina EV, Amendt BA (2002) A molecular basis for differential developmental anomalies in Axenfeld-Rieger syndrome. Hum Mol Genet 11:743–753

    Article  PubMed  CAS  Google Scholar 

  21. Gage PJ, Camper SA (1997) Pituitary homeobox 2, a novel member of the bicoid-related family of homeobox genes, is a potential regulator of anterior structure formation. Hum Mol Genet 6:457–464

    Article  PubMed  CAS  Google Scholar 

  22. Huang Y, Guigon CJ, Fan J, Cheng SY, Zhu GZ (2010) Pituitary homeobox 2 (PITX2) promotes thyroid carcinogenesis by activation of cyclin D2. Cell Cycle 9:1333–1341

    PubMed  CAS  Google Scholar 

  23. Sweeney C, Murphy M, Kubelka M, Ravnik SE, Hawkins CF et al (1996) A distinct cyclin A is expressed in germ cells in the mouse. Development 122:53–64

    PubMed  CAS  Google Scholar 

  24. Ravnik SE, Wolgemuth DJ (1996) The developmentally restricted pattern of expression in the male germ line of a murine cyclin A, cyclin A2, suggests roles in both mitotic and meiotic cell cycles. Dev Biol 173:69–78

    Article  PubMed  CAS  Google Scholar 

  25. Yang R, Morosetti R, Koeffler HP (1997) Characterization of a second human cyclin A that is highly expressed in testis and in several leukemic cell lines. Cancer Res 57:913–920

    PubMed  CAS  Google Scholar 

  26. Ji P, Agrawal S, Diederichs S, Bäumer N, Becker A et al (2005) Cyclin A1, the alternative A-type cyclin, contributes to G1/S cell cycle progression in somatic cells. Oncogene 24:2739–2744

    Article  PubMed  CAS  Google Scholar 

  27. Marlow LA, von Roemeling CA, Cooper SJ, Zhang Y, Rohl SD et al (2012) Foxo3a drives proliferation in anaplastic thyroid carcinoma through transcriptional regulation of cyclin A1: a paradigm shift that impacts current therapeutic strategies. J Cell Sci 125:4253–4263

    Article  PubMed  CAS  Google Scholar 

  28. Muller C, Readhead C, Diederichs S, Idos G, Yang R et al (2000) Methylation of the cyclin A1 promoter correlates with gene silencing in somatic cell lines, while tissue-specific expression of cyclin A1 is methylation independent. Mol Cell Biol 20:3316–3329

    Article  PubMed  CAS  Google Scholar 

  29. Hirose H, Ishii H, Mimori K, Tanaka F, Takemasa I et al (2011) The significance of PITX2 overexpression in human colorectal cancer. Ann Surg Oncol 18:3005–3012

    Article  PubMed  Google Scholar 

  30. Fung FK, Chan DW, Liu VW, Leung TH, Cheung AN et al (2012) Increased expression of PITX2 transcription factor contributes to ovarian cancer progression. PLoS ONE 7(5):e37076

    Article  PubMed  CAS  Google Scholar 

  31. Zhang JX, Tong ZT, Yang L, Wang F, Chai HP et al (2013) PITX2: a promising predictive biomarker of patients’ prognosis and chemoradioresistance in esophageal squamous cell carcinoma. Int J Cancer 132:2567–2577

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was partially supported by the U.S. National Science Foundation under Cooperative Agreement No. EPS-1003907. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation.

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Authors and Affiliations

  1. Department of Ophthalmology, Huashan Hospital Affiliated to Fudan University, 12 Middle Wulumuqi Road, Shanghai, 200040, People’s Republic of China

    Yan Liu

  2. Department of Biology, Marshall University, Huntington, WV, 25755, USA

    Yue Huang & Guo-Zhang Zhu

Authors
  1. Yan Liu
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  2. Yue Huang
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  3. Guo-Zhang Zhu
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Corresponding author

Correspondence to Guo-Zhang Zhu.

Additional information

Yan Liu and Yue Huang have equally contributed to this work.

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Liu, Y., Huang, Y. & Zhu, GZ. Cyclin A1 is a transcriptional target of PITX2 and overexpressed in papillary thyroid carcinoma. Mol Cell Biochem 384, 221–227 (2013). https://doi.org/10.1007/s11010-013-1801-9

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  • DOI: https://doi.org/10.1007/s11010-013-1801-9

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