DOI QR코드

DOI QR Code

ATF3 Activates Stat3 Phosphorylation through Inhibition of p53 Expression in Skin Cancer Cells

  • Hao, Zhen-Feng (Graduate Management Brigade, Third Military Medical University) ;
  • Ao, Jun-Hong (Institute of Skin Damage and Repair, General Hospital of Beijing Region of PLA) ;
  • Zhang, Jie (Institute of Skin Damage and Repair, General Hospital of Beijing Region of PLA) ;
  • Su, You-Ming (Institute of Skin Damage and Repair, General Hospital of Beijing Region of PLA) ;
  • Yang, Rong-Ya (Institute of Skin Damage and Repair, General Hospital of Beijing Region of PLA)
  • Published : 2013.12.31

Abstract

Aim: ATF3, a member of the ATF/CREB family of transcription factors, has been found to be selectively induced by calcineurin/NFAT inhibition and to enhance keratinocyte tumor formation, although the precise role of ATF3 in human skin cancer and possible mechanisms remain unknown. Methods: In this study, clinical analysis of 30 skin cancer patients and 30 normal donors revealed that ATF3 was accumulated in skin cancer tissues. Functional assays demonstrated that ATF3 significantly promoted skin cancer cell proliferation. Results: Mechanically, ATF3 activated Stat3 phosphorylation in skin cancer cell through regulation of p53 expression. Moreover, the promotion effect of ATF3 on skin cancer cell proliferation was dependent on the p53-Stat3 signaling cascade. Conclusion: Together, the results indicate that ATF3 might promote skin cancer cell proliferation and enhance skin keratinocyte tumor development through inhibiting p53 expression and then activating Stat3 phosphorylation.

References

  1. Allan AL, Albanese C, Pestell RG, LaMarre J (2001). Activating transcription factor 3 induces DNA synthesis and expression of cyclin D1 in hepatocytes. J Biol Chem, 276, 27272-80. https://doi.org/10.1074/jbc.M103196200
  2. Allen-Jennings AE, Hartman MG, Kociba GJ, Hai T (2001). The roles of ATF3 in glucose homeostasis. A transgenic mouse model with liver dysfunction and defects in endocrine pancreas. J Biol Chem, 276, 29507-14. https://doi.org/10.1074/jbc.M100986200
  3. Boni R, Schuster C, Nehrhoff B, Burg G (2002). Epidemiology of skin cancer. Neuro Endocrinol Lett, 23, 48-51.
  4. Cai Y, Zhang C, Nawa T, et al (2000). Homocysteine-responsive ATF3 gene expression in human vascular endothelial cells: activation of c-Jun NH(2).-terminal kinase and promoter response element. Blood, 96, 2140-8.
  5. Chen BP, Wolfgang CD, Hai T (1996). Analysis of ATF3, a transcription factor induced by physiological stresses and modulated by gadd153/Chop10. Mol Cell Biol, 16, 1157-68. https://doi.org/10.1128/MCB.16.3.1157
  6. Corvinus FM, Orth C, Moriggl R, et al (2005). Persistent STAT3 activation in colon cancer is associated with enhanced cell proliferation and tumor growth. Neoplasia, 7, 545-55. https://doi.org/10.1593/neo.04571
  7. Diepgen TL, Mahler V (2002). The epidemiology of skin cancer. Br J Dermatol, 146, 1-6.
  8. Fan F, Jin S, Amundson SA, et al (2002). ATF3 induction following DNA damage is regulated by distinct signaling pathways and over-expression of ATF3 protein suppresses cells growth. Oncogene, 21, 7488-96. https://doi.org/10.1038/sj.onc.1205896
  9. Gold ES, Ramsey SA, Sartain MJ, et al (2012). ATF3 protects against atherosclerosis by suppressing 25-hydroxycholesterol-induced lipid body formation. J Exp Med, 209, 807-17. https://doi.org/10.1084/jem.20111202
  10. Gordon R (2013). Skin cancer: an overview of epidemiology and risk factors. Semin Oncol Nurs, 29, 160-9. https://doi.org/10.1016/j.soncn.2013.06.002
  11. Hai T, Hartman MG (2001). The molecular biology and nomenclature of the activating transcription factor/cAMP responsive element binding family of transcription factors: activating transcription factor proteins and homeostasis. Gene, 273, 1-11. https://doi.org/10.1016/S0378-1119(01)00551-0
  12. Hai T, Wolfgang CD, Marsee DK, Allen AE, Sivaprasad U (1999). ATF3 and stress responses. Gene Expr, 7, 321-35.
  13. Hodge DR, Hurt EM, Farrar WL (2005). The role of IL-6 and STAT3 in inflammation and cancer. Eur J Cancer, 41, 2502-12. https://doi.org/10.1016/j.ejca.2005.08.016
  14. Huang X, Li X, Guo B (2008). KLF6 induces apoptosis in prostate cancer cells through up-regulation of ATF3. J Biol Chem, 283, 29795-801. https://doi.org/10.1074/jbc.M802515200
  15. Ishiguro T, Nagawa H (2000). Expression of the ATF3 gene on cell lines and surgically excised specimens. Oncol Res, 12, 181-3.
  16. Ishiguro T, Nagawa H, Naito M, Tsuruo T (2000). Inhibitory effect of ATF3 antisense oligonucleotide on ectopic growth of HT29 human colon cancer cells. Jpn J Cancer Res, 91, 833-6. https://doi.org/10.1111/j.1349-7006.2000.tb01021.x
  17. Jang MK, Kim CH, Seong JK, Jung MH (2012). ATF3 inhibits adipocyte differentiation of 3T3-L1 cells. Biochem Biophys Res Commun, 421, 38-43. https://doi.org/10.1016/j.bbrc.2012.03.104
  18. Kamran MZ, Patil P, Gude RP (2013). Role of STAT3 in Cancer Metastasis and Translational Advances. Biomed Res Int, 2013, 421821.
  19. Kiryu-Seo S, Kato R, Ogawa T, Nakagomi S, Nagata K, Kiyama H (2008). Neuronal injury-inducible gene is synergistically regulated by ATF3, c-Jun, and STAT3 through the interaction with Sp1 in damaged neurons. J Biol Chem, 283, 6988-96. https://doi.org/10.1074/jbc.M707514200
  20. Koike M, Ninomiya Y, Koike A (2005). Characterization of ATF3 induction after ionizing radiation in human skin cells. J Radiat Res, 46, 379-85. https://doi.org/10.1269/jrr.46.379
  21. Kool J, Hamdi M, Cornelissen-Steijger P, van der Eb AJ, Terleth C, van Dam H (2003). Induction of ATF3 by ionizing radiation is mediated via a signaling pathway that includes ATM, Nibrin1, stress-induced MAPkinases and ATF-2. Oncogene, 22, 4235-42. https://doi.org/10.1038/sj.onc.1206611
  22. Lee SH, Min KW, Zhang X, Baek SJ (2013). 3,3'-diindolylmethane induces activating transcription factor 3 (ATF3). via ATF4 in human colorectal cancer cells. J Nutr Biochem, 24, 664-71. https://doi.org/10.1016/j.jnutbio.2012.03.016
  23. Liang G, Wolfgang CD, Chen BP, Chen TH, Hai T (1996). ATF3 gene. Genomic organization, promoter, and regulation. J Biol Chem, 271, 1695-701. https://doi.org/10.1074/jbc.271.3.1695
  24. Lin J, Tang H, Jin X, Jia G, Hsieh JT (2002). p53 regulates Stat3 phosphorylation and DNA binding activity in human prostate cancer cells expressing constitutively active Stat3. Oncogene, 21, 3082-8. https://doi.org/10.1038/sj.onc.1205426
  25. Niu G, Wright KL, Ma Y et al. (2005). Role of Stat3 in regulating p53 expression and function. Mol Cell Biol, 25, 7432-40. https://doi.org/10.1128/MCB.25.17.7432-7440.2005
  26. Perez S, Vial E, van Dam H, Castellazzi M (2001). Transcription factor ATF3 partially transforms chick embryo fibroblasts by promoting growth factor-independent proliferation. Oncogene, 20, 1135-41. https://doi.org/10.1038/sj.onc.1204200
  27. Rose CL, Chakravarti N, Curry JL (2012). The utility of ATF3 in distinguishing cutaneous squamous cell carcinoma among other cutaneous epithelial neoplasms. J Cutan Pathol, 39, 762-8. https://doi.org/10.1111/j.1600-0560.2012.01938.x
  28. Taketani K, Kawauchi J, Tanaka-Okamoto M (2012). Key role of ATF3 in p53-dependent DR5 induction upon DNA damage of human colon cancer cells. Oncogene, 31, 2210-21. https://doi.org/10.1038/onc.2011.397
  29. Tamura K, Hua B, Adachi S et al. (2005). Stress response gene ATF3 is a target of c-myc in serum-induced cell proliferation. EMBO J, 24, 2590-601. https://doi.org/10.1038/sj.emboj.7600742
  30. Thompson MR, Xu D, Williams BR (2009). ATF3 transcription factor and its emerging roles in immunity and cancer. J Mol Med, 87, 1053-60. https://doi.org/10.1007/s00109-009-0520-x
  31. Tsujino H, Kondo E, Fukuoka T, et al (2000). Activating transcription factor 3 (ATF3). induction by axotomy in sensory and motoneurons: A novel neuronal marker of nerve injury. Mol Cell Neurosci, 15, 170-82. https://doi.org/10.1006/mcne.1999.0814
  32. Wang H, Jiang M, Cui H, et al (2012). The stress response mediator ATF3 represses androgen signaling by binding the androgen receptor. Mol Cell Biol, 32, 3190-202. https://doi.org/10.1128/MCB.00159-12
  33. Wolfgang CD, Chen BP, Martindale JL, Holbrook NJ, Hai T (1997). gadd153/Chop10, a potential target gene of the transcriptional repressor ATF3. Mol Cell Biol, 17, 6700-7. https://doi.org/10.1128/MCB.17.11.6700
  34. Wolfgang CD, Liang G, Okamoto Y, Allen AE, Hai T (2000). Transcriptional autorepression of the stress-inducible gene ATF3. J Biol Chem, 275, 16865-70. https://doi.org/10.1074/jbc.M909637199
  35. Wu X, Nguyen BC, Dziunycz P, et al (2010). Opposing roles for calcineurin and ATF3 in squamous skin cancer. Nature, 465, 368-72. https://doi.org/10.1038/nature08996
  36. Yamaue H, Tanimura H, Noguchi K, et al (1992). Chemosensitivity testing of fresh human gastric cancer with highly purified tumour cells using the MTT assay. Br J Cancer, 66, 794-9. https://doi.org/10.1038/bjc.1992.362
  37. Yan C, Lu D, Hai T, Boyd DD (2005). Activating transcription factor 3, a stress sensor, activates p53 by blocking its ubiquitination. EMBO J, 24, 2425-35. https://doi.org/10.1038/sj.emboj.7600712
  38. Yan C, Wang H, Boyd DD (2002). ATF3 represses 72-kDa type IV collagenase (MMP-2). expression by antagonizing p53-dependent trans-activation of the collagenase promoter. J Biol Chem, 277, 10804-12. https://doi.org/10.1074/jbc.M112069200
  39. Yin X, Dewille JW, Hai T (2008). A potential dichotomous role of ATF3, an adaptive-response gene, in cancer development. Oncogene, 27, 2118-27. https://doi.org/10.1038/sj.onc.1210861
  40. Yu H, Pardoll D, Jove R (2009). STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer, 9, 798-809. https://doi.org/10.1038/nrc2734
  41. Zhang C, Kawauchi J, Adachi MT, et al (2001). Activation of JNK and transcriptional repressor ATF3/LRF1 through the IRE1/TRAF2 pathway is implicated in human vascular endothelial cell death by homocysteine. Biochem Biophys Res Commun, 289, 718-24. https://doi.org/10.1006/bbrc.2001.6044

Cited by

  1. Radiation Induces Phosphorylation of STAT3 in a Dose- and Time-dependent Manner vol.15, pp.15, 2014, https://doi.org/10.7314/APJCP.2014.15.15.6161
  2. Anti-VEGF Therapy with Bevacizumab - Limited Cardiovascular Toxicity vol.15, pp.24, 2015, https://doi.org/10.7314/APJCP.2014.15.24.10769
  3. Activating transcription factor 3 interferes with p21 activation in histone deacetylase inhibitor-induced growth inhibition of epidermoid carcinoma cells vol.36, pp.3, 2015, https://doi.org/10.1007/s13277-014-2618-1
  4. Runx2, a target gene for activating transcription factor-3 in human breast cancer cells vol.36, pp.3, 2015, https://doi.org/10.1007/s13277-014-2796-x
  5. Methylisoindigo and Its Bromo-Derivatives Are Selective Tyrosine Kinase Inhibitors, Repressing Cellular Stat3 Activity, and Target CD133+ Cancer Stem Cells in PDAC vol.22, pp.9, 2017, https://doi.org/10.3390/molecules22091546
  6. Activating transcription factor 3 promotes malignance of lung cancer cells in vitro vol.8, pp.3, 2017, https://doi.org/10.1111/1759-7714.12421
  7. Serum and Adipose Tissue mRNA Levels of ATF3 and FNDC5/Irisin in Colorectal Cancer Patients With or Without Obesity vol.9, pp.1664-042X, 2018, https://doi.org/10.3389/fphys.2018.01125