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Curcumin inhibits growth of human breast cancer cells through demethylation of DLC1 promoter

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Abstract

The heterogeneity of breast cancer makes it a challenging solid tumor to diagnose and treat. A tumor suppressor Deleted in Liver Cancer 1 (DLC1) has been reported to be down-regulated or even silenced in several kinds of cancer including breast cancer. Curcumin has been reported to modulate the growth of tumor cells through regulation of multiple cell signaling pathways and modulate epigenetic changes by CpG demethylation of many tumor suppressor genes. This study was designed to investigate the effect of curcumin on the expression of Deleted in Liver Cancer 1 (DLC1) in human breast cancer cell line MDA-MB-361 and the underlying mechanism in vitro and in vivo. Curcumin induced DLC1 expression in a dose-dependent manner. In curcumin-treated cells, methylation of DLC1 promoter was reduced and active forms of RhoA and Cdc42 were also decreased. DLC1 expression was closely related to tumor cell growth, demonstrated by Ki67 staining. Curcumin inhibited DNA methyltransferase 1 expression through down-regulation of transcription factor Sp1. Consistent with the in vitro data, in vivo administration of curcumin inhibited the growth of implanted MDA-MB-361 cells and induced DLC1 expression in tumor tissue. In MDA-MB-361 cells, curcumin down-regulates the expression of Sp1 to inhibit the expression of DNA methyltransferase 1, thus subsequently reducing hypermethylation of DLC1 promoter to induce DLC1 expression.

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References

  1. Hutchinson L (2010) Breast cancer: challenges, controversies, breakthroughs. Nat Rev Clin Oncol 7:669–670

    Article  PubMed  Google Scholar 

  2. Ye Y, Qiu TH, Kavanaugh C, Green JE (2004) Molecular mechanisms of breast cancer progression: lessons from mouse mammary cancer models and gene expression profiling. Breast Dis 19:69–82

    Article  CAS  PubMed  Google Scholar 

  3. Quayle L, Ottewell PD, Holen I (2015) Bone metastasis: molecular mechanisms implicated in tumour cell dormancy in breast and prostate cancer. Curr Cancer Drug Targets 15:469–480

    Article  CAS  PubMed  Google Scholar 

  4. Kozlowski J, Kozlowska A, Kocki J (2015) Breast cancer metastasis—insight into selected molecular mechanisms of the phenomenon. Postepy Hig Med Dosw (Online) 69:447–451

    Article  Google Scholar 

  5. Mego M, Mani SA, Cristofanilli M (2010) Molecular mechanisms of metastasis in breast cancer–clinical applications. Nat Rev Clin Oncol 7:693–701

    Article  CAS  PubMed  Google Scholar 

  6. Yuan BZ, Miller MJ, Keck CL, Zimonjic DB, Thorgeirsson SS, Popescu NC (1998) Cloning, characterization, and chromosomal localization of a gene frequently deleted in human liver cancer (DLC-1) homologous to rat RhoGAP. Cancer Res 58:2196–2199

    CAS  PubMed  Google Scholar 

  7. Lukasik D, Wilczek E, Wasiutynski A, Gornicka B (2011) Deleted in liver cancer protein family in human malignancies (Review). Oncol Lett 2:763–768

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Durkin ME, Yuan BZ, Zhou X et al (2007) DLC-1:a Rho GTPase-activating protein and tumour suppressor. J Cell Mol Med 11:1185–1207

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Sahai E, Marshall CJ (2002) RHO-GTPases and cancer. Nat Rev Cancer 2:133–142

    Article  PubMed  Google Scholar 

  10. Ullmannova V, Popescu NC (2007) Inhibition of cell proliferation, induction of apoptosis, reactivation of DLC1, and modulation of other gene expression by dietary flavone in breast cancer cell lines. Cancer Detect Prev 31:110–118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kim TY, Jong HS, Song SH et al (2003) Transcriptional silencing of the DLC-1 tumor suppressor gene by epigenetic mechanism in gastric cancer cells. Oncogene 22:3943–3951

    Article  CAS  PubMed  Google Scholar 

  12. Ying J, Li H, Murray P et al (2007) Tumor-specific methylation of the 8p22 tumor suppressor gene DLC1 is an epigenetic biomarker for Hodgkin, nasal NK/T-cell and other types of lymphomas. Epigenetics 2:15–21

    Article  PubMed  Google Scholar 

  13. Kulis M, Esteller M (2010) DNA methylation and cancer. Adv Genet 70:27–56

    PubMed  Google Scholar 

  14. Seng TJ, Low JS, Li H et al (2007) The major 8p22 tumor suppressor DLC1 is frequently silenced by methylation in both endemic and sporadic nasopharyngeal, esophageal, and cervical carcinomas, and inhibits tumor cell colony formation. Oncogene 26:934–944

    Article  CAS  PubMed  Google Scholar 

  15. Teramoto A, Tsukuda K, Yano M et al (2004) Less frequent promoter hypermethylation of DLC-1 gene in primary breast cancers. Oncol Rep 12:141–144

    CAS  PubMed  Google Scholar 

  16. Ravindran J, Prasad S, Aggarwal BB (2009) Curcumin and cancer cells: how many ways can curry kill tumor cells selectively? AAPS J 11:495–510

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Guo Y, Shu L, Zhang C, Su ZY, Kong AN (2015) Curcumin inhibits anchorage-independent growth of HT29 human colon cancer cells by targeting epigenetic restoration of the tumor suppressor gene DLEC1. Biochem Pharmacol 94:69–78

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Reuter S, Gupta SC, Park B, Goel A, Aggarwal BB (2011) Epigenetic changes induced by curcumin and other natural compounds. Genes Nutr 6:93–108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Li G, Du X, Vass WC, Papageorge AG, Lowy DR, Qian X (2011) Full activity of the deleted in liver cancer 1 (DLC1) tumor suppressor depends on an LD-like motif that binds talin and focal adhesion kinase (FAK). Proc Natl Acad Sci USA 108:17129–17134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Bar-Sela G, Epelbaum R, Schaffer M (2010) Curcumin as an anti-cancer agent: review of the gap between basic and clinical applications. Curr Med Chem 17:190–197

    Article  CAS  PubMed  Google Scholar 

  21. Wilken R, Veena MS, Wang MB, Srivatsan ES (2011) Curcumin: a review of anti-cancer properties and therapeutic activity in head and neck squamous cell carcinoma. Mol Cancer 10:12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Rahmani AH, Al Zohairy MA, Aly SM, Khan MA (2014) Curcumin: a potential candidate in prevention of cancer via modulation of molecular pathways. Biomed Res Int 2014:761608

    Article  PubMed  PubMed Central  Google Scholar 

  23. Link A, Balaguer F, Shen Y et al (2013) Curcumin modulates DNA methylation in colorectal cancer cells. PLoS ONE 8:e57709

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Vega FM, Ridley AJ (2008) Rho GTPases in cancer cell biology. FEBS Lett 582:2093–2101

    Article  CAS  PubMed  Google Scholar 

  25. Etienne-Manneville S, Hall A (2002) Rho GTPases in cell biology. Nature 420:629–635

    Article  CAS  PubMed  Google Scholar 

  26. Jaffe AB, Hall A (2005) Rho GTPases: biochemistry and biology. Annu Rev Cell Dev Biol 21:247–269

    Article  CAS  PubMed  Google Scholar 

  27. Popescu NC, Goodison S (2014) Deleted in liver cancer-1 (DLC1): an emerging metastasis suppressor gene. Mol Diagn Ther 18:293–302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wang Y, Lei R, Zhuang X et al (2014) DLC1-dependent parathyroid hormone-like hormone inhibition suppresses breast cancer bone metastasis. J Clin Invest 124:1646–1659

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Liu Z, Xie Z, Jones W et al (2009) Curcumin is a potent DNA hypomethylation agent. Bioorg Med Chem Lett 19:706–709

    Article  PubMed  Google Scholar 

  30. Medina-Franco JL, Lopez-Vallejo F, Kuck D, Lyko F (2011) Natural products as DNA methyltransferase inhibitors: a computer-aided discovery approach. Mol Divers 15:293–304

    Article  CAS  PubMed  Google Scholar 

  31. Low JS, Tao Q, Ng KM et al (2011) A novel isoform of the 8p22 tumor suppressor gene DLC1 suppresses tumor growth and is frequently silenced in multiple common tumors. Oncogene 30:1923–1935

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wong CM, Wong CC, Ng YL, Au SL, Ko FC, Ng IO (2011) Transcriptional repressive H3K9 and H3K27 methylations contribute to DNMT1-mediated DNA methylation recovery. PLos ONE 6:e16702

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Pathania R, Ramachandran S, Elangovan S et al (2015) DNMT1 is essential for mammary and cancer stem cell maintenance and tumorigenesis. Nat Commun 6:6910

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Cedar H, Bergman Y (2009) Linking DNA methylation and histone modification: patterns and paradigms. Nat Rev Genet 10:295–304

    Article  CAS  PubMed  Google Scholar 

  35. Irvine RA, Lin IG, Hsieh CL (2002) DNA methylation has a local effect on transcription and histone acetylation. Mol Cell Biol 22:6689–6696

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kishikawa S, Murata T, Kimura H, Shiota K, Yokoyama KK (2002) Regulation of transcription of the Dnmt1 gene by Sp1 and Sp3 zinc finger proteins. Eur J Biochem 269:2961–2970

    Article  CAS  PubMed  Google Scholar 

  37. Kimura H, Nakamura T, Ogawa T, Tanaka S, Shiota K (2003) Transcription of mouse DNA methyltransferase 1 (Dnmt1) is regulated by both E2F-Rb-HDAC-dependent and -independent pathways. Nucleic Acids Res 31:3101–3113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zhang Q, Wang HY, Woetmann A, Raghunath PN, Odum N, Wasik MA (2006) STAT3 induces transcription of the DNA methyltransferase 1 gene (DNMT1) in malignant T lymphocytes. Blood 108:1058–1064

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Li L, Davie JR (2010) The role of Sp1 and Sp3 in normal and cancer cell biology. Ann Anat 192:275–283

    Article  CAS  PubMed  Google Scholar 

  40. Beishline K, Azizkhan-Clifford J (2015) Sp1 and the ‘hallmarks of cancer’. FEBS J 282:224–258

    Article  CAS  PubMed  Google Scholar 

  41. Vizcaino C, Mansilla S, Portugal J (2015) Sp1 transcription factor: a long-standing target in cancer chemotherapy. Pharmacol Ther 152:111–124

    Article  CAS  PubMed  Google Scholar 

  42. Ravi A, Kaushik S, Ravichandran A et al (2015) Epidermal growth factor activates the Rho GTPase-activating protein (GAP) Deleted in Liver Cancer 1 via focal adhesion kinase and protein phosphatase 2A. J Biol Chem 290:4149–4162

    Article  CAS  PubMed  Google Scholar 

  43. Katz M, Amit I, Citri A, Shay T et al (2007) A reciprocal tensin-3-cten switch mediates EGF-driven mammary cell migration. Nat Cell Biol 9:961–969

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by National Science Foundation of China (No.81302269 to J.J. Wang and No. 81550029 to C.F. Yuan) and Natural Science Foundation of Hubei Province of China (No.2011CDB327 to J. Zhou and No. 2015CFB198 to C.F. Yuan).

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    Authors and Affiliations

    1. Institute of Pathology, China Three Gorges University, Yichang, 443000, Hubei, People’s Republic of China

      Yufei Liu & Yuchang Hu

    2. Department of Pathology, Yichang Central People’s Hospital, Yichang, 443003, Hubei, People’s Republic of China

      Yufei Liu & Yuchang Hu

    3. Department of Ultrasound, Yichang Central People’s Hospital, Yichang, 443003, Hubei, People’s Republic of China

      Jun Zhou

    4. Department of Obstetrics and Gynecology, Ren He Hospital of China Three Gorges University, Yichang, 443001, Hubei, People’s Republic of China

      Junjie Wang

    5. Department of Biochemistry, China Three Gorges University, Yichang, 443000, Hubei, People’s Republic of China

      Chengfu Yuan

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    1. Yufei Liu
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    Yufei Liu and Jun Zhou contributed equally to this work.

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    11010_2016_2861_MOESM1_ESM.docx

    Effect of curcumin on expression of DLC1 and DNMT1 in MDA-MB-231 and MCF-7 cells. (A) Representative Western blot images. (B) Statistics of expression of DLC1 and DNMT1. N = 5 per group. *p < 0.05; **p < 0.01; ***p < 0.001 compared with “0” group

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    Liu, Y., Zhou, J., Hu, Y. et al. Curcumin inhibits growth of human breast cancer cells through demethylation of DLC1 promoter. Mol Cell Biochem 425, 47–58 (2017). https://doi.org/10.1007/s11010-016-2861-4

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    • DOI: https://doi.org/10.1007/s11010-016-2861-4

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