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Med19 promotes breast cancer cell proliferation by regulating CBFA2T3/HEB expression

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Abstract

Background

Mediator complex 19 (Med19) is a pivotal subunit of the Mediator complex, and its aberrant expression is involved in tumourigenesis. We aimed to explore the mechanism by which Med19 promotes the proliferation of breast cancer.

Methods

Lentivirus-mediated inhibition of Med19, ectopic expression of Med19 and ectopic expression of core-binding factor subunit alpha 2 to translocation 3 (CBFA2T3) were applied in human breast cancer cell lines. Human breast cancer cell proliferation was determined using CCK8 and colony formation assays after lentivirus infection. The expression of Med19, CBFA2T3 and HEB was measured by real-time reverse transcription polymerase chain reaction and Western blotting. The correlation between Med19 and CBFA2T3 expression in tissue from 25 cases of human breast cancer was analysed.

Results

In this study, we demonstrate that cell proliferation and colony formation capacity were significantly inhibited after Med19 inhibition in vitro. The expression of CBFA2T3 was distinctly up-regulated in MDA-MB-231 and MCF-7 human breast cancer cells when Med19 was knocked down; however, the expression of HEB, which is targeted by CBFA2T3, was down-regulated. Meanwhile, ectopic expression of Med19 in BT-549 and Hs578T human breast cancer cells inhibited CBFA2T3 expression but enhanced HEB expression. The proliferation capacity of human breast cancer cells was increased when Med19 was overexpressed, but the effect of Med19 up-regulation could be reversed by CBFA2T3 overexpression. Furthermore, a negative correlation between Med19 and CBFA2T3 expression was demonstrated by Western blotting in human breast cancer tissue.

Conclusions

These results suggest that Med19 promotes breast cancer cell proliferation and that this effect is associated with CBFA2T3 and HEB. These results provide new insights into the potential role of Med19 in the regulation of breast carcinogenesis, and Med19 may be a useful therapeutic target in breast cancer therapy.

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References

  1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108.

    Article  PubMed  Google Scholar 

  2. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136:E359–86.

    Article  CAS  PubMed  Google Scholar 

  3. Guglielmi B, Van Berkum NL, Klapholz B, Bijma T, Boube M, Boschiero C, et al. A high resolution protein interaction map of the yeast mediator complex. Nucl Acid Res. 2004;32:5379–91.

    Article  CAS  Google Scholar 

  4. Chadick JZ, Asturias FJ. Structure of eukaryotic mediator complexes. Trends Biochem Sci. 2005;30:264–71.

    Article  CAS  PubMed  Google Scholar 

  5. Conaway RC, Conaway JW. The mediator complex and transcription elongation. Biochim Biophys Acta. 2013;1829:69–75.

    Article  CAS  PubMed  Google Scholar 

  6. Schiano C, Casamassimi A, Rienzo M, De Nigris F, Sommese L, Napoli C. Involvement of mediator complex in malignancy. Biochim Biophys Acta. 2014;1845:66–83.

    CAS  PubMed  Google Scholar 

  7. Rosenblum-Vos LS, Rhodes L, Evangelista CC Jr, Boayke KA, Zitomer RS. The ROX3 gene encodes an essential nuclear protein involved in CYC7 gene expression in Saccharomyces cerevisiae. Mol Cell Biol. 1991;11:5639–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Li LH, He J, Hua D, Guo ZJ, Gao Q. Lentivirus-mediated inhibition of Med19 suppresses growth of breast cancer cells in vitro. Cancer Chemother Pharmacol. 2011;68:207–15.

    Article  PubMed  Google Scholar 

  9. Ding XF, Huang GM, Shi Y, Li JA, Fang XD. Med19 promotes gastric cancer progression and cellular growth. Gene. 2012;504:262–7.

    Article  CAS  PubMed  Google Scholar 

  10. Ji-Fu E, Xing JJ, Hao LQ, Fu CG. Suppression of lung cancer metastasis: related protein 1 (LCMR1) inhibits the growth of colorectal cancer cells. Mol Biol Rep. 2012;39:3675–81.

    Article  CAS  PubMed  Google Scholar 

  11. Xu Y, Li C, Tian Q, Li Y, Yang Z, Liang Z, et al. Suppression of lung cancer metastasis-related protein 1 promotes apoptosis in lung cancer cells. Int J Mol Med. 2012;30:1481–6.

    CAS  PubMed  Google Scholar 

  12. Kochetkova M, Mckenzie OL, Bais AJ, Martin JM, Secker GA, Seshadri R, et al. CBFA2T3 (MTG16) is a putative breast tumor suppressor gene from the breast cancer loss of heterozygosity region at 16q24.3. Cancer Res. 2002;62:4599–604.

    CAS  PubMed  Google Scholar 

  13. Cleton-Jansen AM, Callen DF, Seshadri R, Goldup S, Mccallum B, Crawford J, et al. Loss of heterozygosity mapping at chromosome arm 16q in 712 breast tumors reveals factors that influence delineation of candidate regions. Cancer Res. 2001;61:1171–7.

    CAS  PubMed  Google Scholar 

  14. Salah Z, Arafeh R, Maximov V, Galasso M, Khawaled S, Abou-Sharieha S, et al. miR-27a and miR-27a* contribute to metastatic properties of osteosarcoma cells. Oncotarget. 2015;6:4920–35.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Kumar R, Cheney KM, Mckirdy R, Neilsen PM, Schulz RB, Lee J, et al. CBFA2T3-ZNF652 corepressor complex regulates transcription of the E-box gene HEB. J Biol Chem. 2008;283:19026–38.

    Article  CAS  PubMed  Google Scholar 

  16. Li XH, Fang DN, Zeng CM. Knockdown of MED19 by short hairpin RNA-mediated gene silencing inhibits pancreatic cancer cell proliferation. Cancer Biother Radiopharm. 2011;26:495–501.

    Article  CAS  PubMed  Google Scholar 

  17. Cui X, Xu D, Lv C, Qu F, He J, Chen M, et al. Suppression of MED19 expression by shRNA induces inhibition of cell proliferation and tumorigenesis in human prostate cancer cells. BMB Rep. 2011;44:547–52.

    Article  CAS  PubMed  Google Scholar 

  18. Wang T, Hao L, Feng Y, Wang G, Qin D, Gu G. Knockdown of MED19 by lentivirus-mediated shRNA in human osteosarcoma cells inhibits cell proliferation by inducing cell cycle arrest in the G0/G1 phase. Oncol Res. 2011;19:193–201.

    Article  PubMed  Google Scholar 

  19. Wei L, Wang XW, Sun JJ, Lv LY, Xie L, Song XR. Knockdown of Med19 suppresses proliferation and enhances chemo-sensitivity to cisplatin in non-small cell lung cancer cells. Asian Pac J Cancer Prev. 2015;16:875–80.

    Article  PubMed  Google Scholar 

  20. Kumar R, Cheney KM, Neilsen PM, Schulz RB, Callen DF. CBFA2T3- ZNF651, like CBFA2T3-ZNF652, functions as a transcriptional corepressor complex. FEBS Lett. 2010;584:859–64.

    Article  CAS  PubMed  Google Scholar 

  21. Barrett CW, Smith JJ, Lu LC, Markham N, Stengel KR, Short SP, et al. Kaiso directs the transcriptional corepressor MTG16 to the Kaiso binding site in target promoters. PLoS One. 2012;7:e51205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Asirvatham AL, Galligan SG, Schillace RV, Davey MP, Vasta V, Beavo JA, et al. A-kinase anchoring proteins interact with phosphodiesterases in T lymphocyte cell lines. J Immunol. 2004;173:4806–14.

    Article  CAS  PubMed  Google Scholar 

  23. Fiedler SE, Schillace RV, Daniels CJ, Andrews SF, Carr DW. Myeloid translocation gene 16b is a dual A-kinase anchoring protein that interacts selectively with plexins in a phospho-regulated manner. FEBS Lett. 2010;584:873–7.

    Article  CAS  PubMed  Google Scholar 

  24. Gamou T, Kitamura E, Hosoda F, Shimizu K, Shinohara K, Hayashi Y, et al. The partner gene of AML1 in t(16;21) myeloid malignancies is a novel member of the MTG8(ETO) family. Blood. 1998;91:4028–37.

    CAS  PubMed  Google Scholar 

  25. Chyla BJ, Moreno-Miralles I, Steapleton MA, Thompson MA, Bhaskara S, Engel M, et al. Deletion of Mtg16, a target of t(16;21), alters hematopoietic progenitor cell proliferation and lineage allocation. Mol Cell Biol. 2008;28:6234–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Micci F, Thorsen J, Panagopoulos I, Nyquist KB, Zeller B, Tierens A, et al. High-throughput sequencing identifies an NFIA/CBFA2T3 fusion gene in acute erythroid leukemia with t(1;16)(p31;q24). Leukemia. 2013;27:980–2.

    Article  CAS  PubMed  Google Scholar 

  27. Gruber TA, Larson Gedman A, Zhang J, Koss CS, Marada S, Ta HQ, et al. An Inv(16)(p13.3q24.3)-encoded CBFA2T3-GLIS2 fusion protein defines an aggressive subtype of pediatric acute megakaryoblastic leukemia. Cancer Cell. 2012;22:683–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Rossetti S, Hoogeveen AT, Esposito J, Sacchi N. Loss of MTG16a (CBFA2T3), a novel rDNA repressor, leads to increased ribogenesis and disruption of breast acinar morphogenesis. J Cell Mol Med. 2010;14:1358–70.

    Article  CAS  PubMed  Google Scholar 

  29. Kumar R, Manning J, Spendlove HE, Kremmidiotis G, Mckirdy R, Lee J, et al. ZNF652, a novel zinc finger protein, interacts with the putative breast tumor suppressor CBFA2T3 to repress transcription. Mol Cancer Res. 2006;4:655–65.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by Grants from the Natural Science Foundation of China (81472485), the Project of Six Talent Peaks of Jiangsu Province (WSW-014), and the Project of Hospital Management Center of Wuxi (YGZXQ1311, YGZXM14038).

Author information

Authors and Affiliations

  1. Oncology Institute, The Affiliated Hospital of Jiangnan University, 200# Huihe Road, Wuxi, 214062, Jiangsu, China

    Xiufen Zhang, Beibei Liu & Lihua Li

  2. Department of Haematology and Oncology, Jinxiang Hospital Affiliated with Jining Medical University, Jinxiang, 272200, China

    Yanling Fan

  3. Department of Pathology, the Affiliated Hospital of Jiangnan University, Wuxi, 214062, China

    Xiaowei Qi

  4. Department of Oncological Surgery, the Affiliated Hospital of Jiangnan University, Wuxi, 214062, China

    Zijian Guo

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  1. Xiufen Zhang
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  2. Yanling Fan
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  3. Beibei Liu
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  4. Xiaowei Qi
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  5. Zijian Guo
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Corresponding authors

Correspondence to Xiaowei Qi, Zijian Guo or Lihua Li.

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Yanling Fan: Co-first author.

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Zhang, X., Fan, Y., Liu, B. et al. Med19 promotes breast cancer cell proliferation by regulating CBFA2T3/HEB expression. Breast Cancer 24, 433–441 (2017). https://doi.org/10.1007/s12282-016-0722-3

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  • DOI: https://doi.org/10.1007/s12282-016-0722-3

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