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The DEAD box protein p68: a novel coactivator of Stat3 in mediating oncogenesis

Oncogene volume 36, pages 3080–3093 (2017)Cite this article

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Abstract

DEAD box RNA helicase p68 acts as a transcriptional coactivator of several oncogenic transcription factors apart from being a vital player of RNA metabolism. Signal transducer and activator of transcription 3 (Stat3) is a major oncogenic contributor of diverse cancers, including that of colon. Deciphering the mechanistic insights of coactivation of Stat3 transcriptional activity may aid in improved therapeutic strategies. Here we report for the first time a novel mechanism of alliance between p68 and Stat3 in stimulating transcriptional activity of Stat3. Interestingly, we observed that the expression of p68 and Stat3 bears strong positive correlation and significant colocalization in normal and colon carcinoma patient samples. We demonstrated that p68 directly interacts with Stat3 in HEK293 cells as well as multiple colon cancer cell lines. Additionally, p68 positively modulated both mRNA and protein expression levels of Stat3 target genes; promoter activity of Stat3 target gene Mcl-1 in multiple colon cancer cell lines. Also, p68 occupied the promoters of multiple Stat3 target genes in enhancing Stat3-dependent transcription. Moreover, the strong positive correlation between the abundance of p68 and Stat3 target genes in the same set of colon carcinoma samples further supported our observations. Enhanced expression levels of Stat3 target genes observed in primary tumors and metastatic lung nodules, generated in mice colorectal allograft model using syngeneic cells stably expressing p68, further reinforced our in vitro findings. Hence, this study unravels novel modes of p68-mediated oncogenesis through coactivation of Stat3 and enhancing Stat3 signaling.

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References

  1. Janknecht R . Multi-talented DEAD-box proteins and potential tumor promoters: p68 RNA helicase (DDX5) and its paralog, p72 RNA helicase (DDX17). Am J Transl Res 2010; 2: 223–234.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Fuller-Pace FV, Moore HC . RNA helicases p68 and p72: multifunctional proteins with important implications for cancer development. Future Oncol 2011; 7: 239–251.

    Article  CAS  Google Scholar 

  3. Dai T-Y, Cao L, Yang Z-C, Li Y-S, Tan L, Ran X-Z et al. P68 RNA helicase as a molecular target for cancer therapy. J Exp Clin Cancer Res 2014; 33: 64.

    Article  Google Scholar 

  4. Sarkar M, Ghosh MK . DEAD box RNA helicases: crucial regulators of gene expression and oncogenesis. Front Biosci Landmark Ed 2016; 21: 225–250.

    Article  CAS  Google Scholar 

  5. Yu H, Lee H, Herrmann A, Buettner R, Jove R . Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nat Rev Cancer 2014; 14: 736–746.

    Article  CAS  Google Scholar 

  6. Kamran MZ, Patil P, Gude RP . Role of STAT3 in cancer metastasis and translational advances. BioMed Res Int 2013; 2013: e421821.

    Article  Google Scholar 

  7. Carpenter RL, Lo H-W . STAT3 target genes relevant to human cancers. Cancers 2014; 6: 897–925.

    Article  CAS  Google Scholar 

  8. Sun Y-M . The IL-6/JAK/STAT3 pathway: potential therapeutic strategies in treating colorectal cancer (Review). Int J Oncol 2014; 44: 1032–1040.

    Article  Google Scholar 

  9. Henderson-Jackson EB, Helm J, Ghayouri M, Hakam A, Nasir A, Leon M et al. Correlation between Mcl-1 and pAKT protein expression in colorectal cancer. Int J Clin Exp Pathol 2010; 3: 768–774.

    PubMed  PubMed Central  Google Scholar 

  10. Lee W-S, Park Y-L, Kim N, Oh H-H, Son D-J, Kim M-Y et al. Myeloid cell leukemia-1 is associated with tumor progression by inhibiting apoptosis and enhancing angiogenesis in colorectal cancer. Am J Cancer Res 2014; 5: 101–113.

    PubMed  PubMed Central  Google Scholar 

  11. Zhang Y-L, Pang L-Q, Wu Y, Wang X-Y, Wang C-Q, Fan Y . Significance of Bcl-xL in human colon carcinoma. World J Gastroenterol WJG 2008; 14: 3069–3073.

    Article  CAS  Google Scholar 

  12. Jin-Song Y, Zhao-Xia W, Cheng-Yu L, Xiao-Di L, Ming S, Yuan-Yuan G et al. Prognostic significance of Bcl-xL gene expression in human colorectal cancer. Acta Histochem 2011; 113: 810–814.

    Article  Google Scholar 

  13. Cao D, Hou M, Guan Y, Jiang M, Yang Y, Gou H . Expression of HIF-1alpha and VEGF in colorectal cancer: association with clinical outcomes and prognostic implications. BMC Cancer 2009; 9: 432.

    Article  Google Scholar 

  14. Bendardaf R, Buhmeida A, Hilska M, Laato M, Syrjänen S, Syrjänen K et al. VEGF-1 expression in colorectal cancer is associated with disease localization, stage, and long-term disease-specific survival. Anticancer Res 2008; 28: 3865–3870.

    PubMed  Google Scholar 

  15. Langers AMJ, Verspaget HW, Hawinkels LJAC, Kubben FJGM, van Duijn W, van der Reijden JJ et al. MMP-2 and MMP-9 in normal mucosa are independently associated with outcome of colorectal cancer patients. Br J Cancer 2012; 106: 1495–1498.

    Article  CAS  Google Scholar 

  16. Said AH, Raufman J-P, Xie G . The role of matrix metalloproteinases in colorectal cancer. Cancers 2014; 6: 366–375.

    Article  CAS  Google Scholar 

  17. Iwamoto M, Ahnen DJ, Franklin WA, Maltzman TH . Expression of β-catenin and full-length APC protein in normal and neoplastic colonic tissues. Carcinogenesis 2000; 21: 1935–1940.

    Article  CAS  Google Scholar 

  18. Shin S, Rossow KL, Grande JP, Janknecht R . Involvement of RNA helicases p68 and p72 in colon cancer. Cancer Res 2007; 67: 7572–7578.

    Article  CAS  Google Scholar 

  19. Sarkar M, Khare V, Guturi KKN, Das N, Ghosh MK . The DEAD box protein p68: a crucial regulator of AKT/FOXO3a signaling axis in oncogenesis. Oncogene 2015; 34: 5843–5856.

    Article  CAS  Google Scholar 

  20. Lassmann S, Schuster I, Walch A, Göbel H, Jütting U, Makowiec F et al. STAT3 mRNA and protein expression in colorectal cancer: effects on STAT3-inducible targets linked to cell survival and proliferation. J Clin Pathol 2007; 60: 173–179.

    Article  CAS  Google Scholar 

  21. Gordziel C, Bratsch J, Moriggl R, Knösel T, Friedrich K . Both STAT1 and STAT3 are favourable prognostic determinants in colorectal carcinoma. Br J Cancer 2013; 109: 138–146.

    Article  CAS  Google Scholar 

  22. Akgul C, Turner PC, White MR, Edwards SW . Functional analysis of the human MCL-1 gene. Cell Mol Life Sci CMLS 2000; 57: 684–691.

    Article  CAS  Google Scholar 

  23. Isomoto H, Kobayashi S, Werneburg NW, Bronk SF, Guicciardi ME, Frank DA et al. Interleukin 6 upregulates myeloid cell leukemia-1 expression through a STAT3 pathway in cholangiocarcinoma cells. Hepatology 2005; 42: 1329–1338.

    Article  CAS  Google Scholar 

  24. Sagawa M, Nakazato T, Uchida H, Ikeda Y, Kizaki M . Cantharidin induces apoptosis of human multiple myeloma cells via inhibition of the JAK/STAT pathway. Cancer Sci 2008; 99: 1820–1826.

    Article  CAS  Google Scholar 

  25. Catlett-Falcone R, Landowski TH, Oshiro MM, Turkson J, Levitzki A, Savino R et al. Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity 1999; 10: 105–115.

    Article  CAS  Google Scholar 

  26. Niu G, Wright KL, Huang M, Song L, Haura E, Turkson J et al. Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene 2002; 21: 2000–2008.

    Article  CAS  Google Scholar 

  27. Leslie K, Lang C, Devgan G, Azare J, Berishaj M, Gerald W et al. Cyclin D1 is transcriptionally regulated by and required for transformation by activated signal transducer and activator of transcription 3. Cancer Res 2006; 66: 2544–2552.

    Article  CAS  Google Scholar 

  28. Xie T, Wei D, Liu M, Gao AC, Ali-Osman F, Sawaya R et al. Stat3 activation regulates the expression of matrix metalloproteinase-2 and tumor invasion and metastasis. Oncogene 2004; 23: 3550–3560.

    Article  CAS  Google Scholar 

  29. Dechow TN, Pedranzini L, Leitch A, Leslie K, Gerald WL, Linkov I et al. Requirement of matrix metalloproteinase-9 for the transformation of human mammary epithelial cells by Stat3-C. Proc Natl Acad Sci USA 2004; 101: 10602–10607.

    Article  CAS  Google Scholar 

  30. Song Y, Qian L, Song S, Chen L, Zhang Y, Yuan G et al. Fra-1 and Stat3 synergistically regulate activation of human MMP-9 gene. Mol Immunol 2008; 45: 137–143.

    Article  CAS  Google Scholar 

  31. Tetsu O, McCormick F . Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 1999; 398: 422–426.

    Article  CAS  Google Scholar 

  32. Siddiquee KAZ, Turkson J . STAT3 as a target for inducing apoptosis in solid and hematological tumors. Cell Res 2008; 18: 254–267.

    Article  Google Scholar 

  33. Yue P, Turkson J . Targeting STAT3 in cancer: how successful are we? Expert Opin Investig Drugs 2009; 18: 45–56.

    Article  CAS  Google Scholar 

  34. Thakur R, Mishra DP . Pharmacological modulation of beta-catenin and its applications in cancer therapy. J Cell Mol Med 2013; 17: 449–456.

    Article  CAS  Google Scholar 

  35. Bhattacharya S, Ghosh MK . HAUSP regulates c-MYC expression via de-ubiquitination of TRRAP. Cell Oncol 2015; 38: 265–277.

    Article  CAS  Google Scholar 

  36. Ghosh MK, Sharma P, Harbor PC, Rahaman SO, Haque SJ . PI3K-AKT pathway negatively controls EGFR-dependent DNA-binding activity of Stat3 in glioblastoma multiforme cells. Oncogene 2005; 24: 7290–7300.

    Article  CAS  Google Scholar 

  37. Ahmed SF, Das N, Sarkar M, Chatterjee U, Chatterjee S, Ghosh MK . Exosome-mediated delivery of the intrinsic c-terminus domain of PTEN protects it from proteasomal degradation and ablates tumorigenesis. Mol Ther J Am Soc Gene Ther 2015; 23: 255–269.

    Article  CAS  Google Scholar 

  38. Chatterjee A, Chatterjee U, Ghosh MK . Activation of protein kinase CK2 attenuates FOXO3a functioning in a PML-dependent manner: implications in human prostate cancer. Cell Death Dis 2013; 4: e543.

    Article  CAS  Google Scholar 

  39. Bhattacharya S, Ghosh MK . HAUSP, a novel deubiquitinase for Rb - MDM2 the critical regulator. FEBS J 2014; 281: 3061–3078.

    Article  CAS  Google Scholar 

  40. Mandal T, Bhowmik A, Chatterjee A, Chatterjee U, Chatterjee S, Ghosh MK . Reduced phosphorylation of Stat3 at Ser-727 mediated by casein kinase 2—Protein phosphatase 2A enhances Stat3 Tyr-705 induced tumorigenic potential of glioma cells. Cell Signal 2014; 26: 1725–1734.

    Article  CAS  Google Scholar 

  41. Cai B-H, Hsu P-C, Hsin I-L, Chao C-F, Lu M-H, Lin H-C et al. p53 acts as a co-repressor to regulate keratin 14 expression during epidermal cell differentiation. PLoS One 2012; 7: e41742.

    Article  CAS  Google Scholar 

  42. Guturi KK, Sarkar M, Bhowmik A, Das N, Ghosh MK . DEAD-box protein p68 is regulated by β-catenin/transcription factor 4 to maintain a positive feedback loop in control of breast cancer progression. Breast Cancer Res 2014; 16: 496.

    Article  Google Scholar 

  43. Sha J, Ghosh MK, Zhang K, Harter ML . E1A interacts with two opposing transcriptional pathways to induce quiescent cells into S phase. J Virol 2010; 84: 4050–4059.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Dr Frances V Fuller-Pace and Dr Kenneth M Yamada for gifting the pGS5-p68 construct and pGZ21dx vector, respectively. We also thank Dr Uttara Chatterjee (Park Clinic, India) for providing human normal colon and colon carcinoma samples, related pathological reports and helping in the data analysis. This work is supported by grants from CSIR, India (EMPOWER-OLP-002, MEDCHEM-BSC0108 and CSIR-MAYO Clinic programme: MLP-0017) and DST Nano Mission programme (SR/NM/NS-1058/2015) to Dr Mrinal K Ghosh.

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Authors and Affiliations

  1. Cancer Biology and Inflammatory Disorder Division, Signal Transduction in Cancer and Stem Cells Laboratory, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), Kolkata, India

    M Sarkar, V Khare & M K Ghosh

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  1. M Sarkar
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Correspondence to M K Ghosh.

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Sarkar, M., Khare, V. & Ghosh, M. The DEAD box protein p68: a novel coactivator of Stat3 in mediating oncogenesis. Oncogene 36, 3080–3093 (2017). https://doi.org/10.1038/onc.2016.449

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