Translational Therapeutics

DAXX inhibits cancer stemness and epithelial–mesenchymal transition in gastric cancer

Abstract

Background

DAXX is a transcription repressor that has been implicated in several types of cancers, but its role in the development of gastric cancer remains unknown.

Methods

We analysed the expression of DAXX in 83 pairs of gastric cancer samples, including neoplastic and adjacent tissues, and correlated the expression levels with clinical stages. We also investigated the molecular mechanisms by which DAXX downregulation promotes cancer growth using both in vitro and in vivo models.

Results

DAXX was downregulated in advanced gastric cancer samples. The expression of DAXX inversely correlates with that of cancer stem cell markers CD44 and Oct4 in gastric cancer lines. DAXX overexpression in gastric cancer cells inhibited migration, invasion and epithelial– mesenchymal transition (EMT). The inhibition of EMT was achieved through the repression of SNAI3, a key inducer of EMT, by recruiting HDAC-1 into the nucleus. Using a xenograft mouse model, we demonstrated that the MKN45 cells formed smaller tumours when DAXX was overexpressed. Wild-type AGS cells were not able to form tumours in nude mice, but in contrast, formed visible tumours when DAXX was silenced in the cells.

Conclusion

We for the first time demonstrated that DAXX functions as a tumour suppressor in gastric cancer by inhibiting stem cell growth and EMT.

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Fig. 1: DAXX expression in gastric cancer primary samples from patients.
Fig. 2: The expression of DAXX, CD44 and Oct4 in gastric cancer cell lines.
Fig. 3: The effect of DAXX on migration and invasion of gastric cancer cells.
Fig. 4: DAXX inhibits EMT of gastric cancer cells.
Fig. 5: DAXX inhibits SNAI3 transcription by recruiting HDAC-1 into the nucleus.
Fig. 6: Effect of DAXX on anchorage-independent growth of gastric cancer cells.

References

  1. 1.

    Benitez, J. A., Ma, J., D’Antonio, M., Boyer, A., Camargo, M. F., Zanca, C. et al. PTEN regulates glioblastoma oncogenesis through chromatin-associated complexes of DAXX and histone H3.3. Nat. Commun. 8, 15223 (2017).

  2. 2.

    Pan, W. W., Zhou, J. J., Liu, X. M., Xu, Y., Guo, L. J., Yu, C. et al. Death domain-associated protein DAXX promotes ovarian cancer development and chemoresistance. J. Biol. Chem. 288, 13620–13630 (2013).

  3. 3.

    Puto, L. A., Brognard, J. & Hunter, T. Transcriptional repressor DAXX promotes prostate cancer tumorigenicity via suppression of autophagy. J. Biol. Chem. 290, 15406–15420 (2015).

  4. 4.

    Marinoni, I., Kurrer, A. S., Vassella, E., Dettmer, M., Rudolph, T., Banz, V. et al. Loss of DAXX and ATRX are associated with chromosome instability and reduced survival of patients with pancreatic neuroendocrine tumors. Gastroenterology 146, 453–60 e5 (2014).

  5. 5.

    Feng, Z., Wang, L., Sun, Y., Jiang, Z., Domsic, J., An, C. et al. Menin and Daxx interact to suppress neuroendocrine tumors through epigenetic control of the membrane metallo-endopeptidase. Cancer Res. 77, 401–411 (2017).

  6. 6.

    Peiffer, D. S., Wyatt, D., Zlobin, A., Piracha, A., Ng, J., Dingwall, A. K. et al. DAXX Suppresses tumor-initiating cells in estrogen receptor-positive breast cancer following endocrine therapy. Cancer Res. 79, 4965–4977 (2019).

  7. 7.

    Kodama, H., Murata, S., Ishida, M., Yamamoto, H., Yamaguchi, T., Kaida, S. et al. Prognostic impact of CD44-positive cancer stem-like cells at the invasive front of gastric cancer. Br. J. cancer 116, 186–194 (2017).

  8. 8.

    Li, N., Deng, W., Ma, J., Wei, B., Guo, K., Shen, W. et al. Prognostic evaluation of Nanog, Oct4, Sox2, PCNA, Ki67 and E-cadherin expression in gastric cancer. Med Oncol. 32, 433 (2015).

  9. 9.

    Lin, C. W., Wang, L. K., Wang, S. P., Chang, Y. L., Wu, Y. Y., Chen, H. Y. et al. Daxx inhibits hypoxia-induced lung cancer cell metastasis by suppressing the HIF-1alpha/HDAC1/Slug axis. Nat. Commun. 7, 13867 (2016).

  10. 10.

    Bao, M., Liu, S., Yu, X. Y., Wu, C., Chen, Q., Ding, H. et al. Runx1 promotes satellite cell proliferation during ischemia—Induced muscle regeneration. Biochemical biophysical Res. Commun. 503, 2993–2997 (2018).

  11. 11.

    Shen, C., Zhou, J., Wang, X., Yu, X. Y., Liang, C., Liu, B. et al. Angiotensin-II-induced muscle wasting is mediated by 25-hydroxycholesterol via GSK3beta signaling pathway. EBioMedicine 16, 238–250 (2017).

  12. 12.

    Yue, Y., Wang, Y., He, Y., Yang, S., Chen, Z., Xing, S. et al. Reversal of bortezomib resistance in myelodysplastic syndrome cells by MAPK inhibitors. PloS one 9, e90992 (2014).

  13. 13.

    Wang, X., Zhi, Q., Liu, S., Xue, S. L., Shen, C., Li, Y. et al. Identification of specific biomarkers for gastric adenocarcinoma by ITRAQ proteomic approach. Sci. Rep. 6, 38871 (2016).

  14. 14.

    Horibata S., Vo T. V., Subramanian V., Thompson P. R., Coonrod S. A. Utilization of the soft agar colony formation assay to identify inhibitors of tumorigenicity in breast cancer cells. J. Vis. Exp. 20, e52727 (2015)

  15. 15.

    Dai, X., Gan, W., Li, X., Wang, S., Zhang, W., Huang, L. et al. Prostate cancer-associated SPOP mutations confer resistance to BET inhibitors through stabilization of BRD4. Nat. Med. 23, 1063–1071 (2017).

  16. 16.

    Takaishi, S., Okumura, T., Tu, S., Wang, S. S., Shibata, W., Vigneshwaran, R. et al. Identification of gastric cancer stem cells using the cell surface marker CD44. Stem Cells 27, 1006–1020 (2009).

  17. 17.

    Al-Hajj, M., Wicha, M. S., Benito-Hernandez, A., Morrison, S. J. & Clarke, M. F. Prospective identification of tumorigenic breast cancer cells. Proc. Natl Acad. Sci. USA 100, 3983–3988 (2003).

  18. 18.

    George, J. T., Jolly, M. K., Xu, S., Somarelli, J. A. & Levine, H. Survival outcomes in cancer patients predicted by a partial EMT gene expression scoring metric. Cancer Res. 77, 6415–6428 (2017).

  19. 19.

    Mishra, V. K., Subramaniam, M., Kari, V., Pitel, K. S., Baumgart, S. J., Naylor, R. M. et al. Kruppel-like transcription factor KLF10 suppresses TGFbeta-induced epithelial-to-mesenchymal transition via a negative feedback mechanism. Cancer Res. 77, 2387–2400 (2017).

  20. 20.

    Zhong, S., Salomoni, P., Ronchetti, S., Guo, A., Ruggero, D. & Pandolfi, P. P. Promyelocytic leukemia protein (PML) and Daxx participate in a novel nuclear pathway for apoptosis. J. Exp. Med. 191, 631–640 (2000).

  21. 21.

    Song, J. J. & Lee, Y. J. Catalase, but not MnSOD, inhibits glucose deprivation-activated ASK1-MEK-MAPK signal transduction pathway and prevents relocalization of Daxx: hydrogen peroxide as a major second messenger of metabolic oxidative stress. J. Cell. Biochem. 90, 304–314 (2003).

  22. 22.

    Mooney, S. M., Jolly, M. K., Levine, H. & Kulkarni, P. Phenotypic plasticity in prostate cancer: role of intrinsically disordered proteins. Asian J. Androl. 18, 704–710 (2016).

  23. 23.

    Gupta, A., Hou, R., Liu, L., Hiroyasu, S., Hadix, J. A., Huggins, G. S. et al. Daxx inhibits muscle differentiation by repressing E2A-mediated transcription. J. Cell. Biochem. 107, 438–447 (2009).

  24. 24.

    Fang, H. T., El Farran, C. A., Xing, Q. R., Zhang, L. F., Li, H., Lim, B. et al. Global H3.3 dynamic deposition defines its bimodal role in cell fate transition. Nat. Commun. 9, 1537 (2018).

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Acknowledgements

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Author information

Conception and design of the study: C.F.W., Y.L., Y.H.S. and J.Z. Acquisition of data, or analysis and interpretation of data: C.F.W., H.D., S.C.W., S.B.L., X.X.W., J.Q.Z., T.X., Y.L., Y.H.S. and J.Z. Drafting the paper or revising it critically for important intellectual content: C.W., J.Z., H.M.A., Y.L., Y.H.S. and J.Z. Final approval of the version to be submitted: all authors.

Correspondence to Yao-Hua Song or Jin Zhou.

Ethics declarations

Ethics approval and consent to participate

All experiments involving human subjects were performed in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki), and the relevant guidelines and regulations of Soochow University. All experimental protocols were approved by the Research Ethics Committee of the First Affiliated Hospital of Soochow University. With informed consents from all subjects, paired specimens of GC and adjacent normal tissues were collected from patients who underwent surgical resection. None of the patients received anticancer therapy before surgery. Animal experiments complied with the ARRIVE guidelines, and were carried out in accordance with the National Institutes of Health guidelines for the care and use of laboratory animals (NIH Publications No. 8023, revised 1978).

Data availability

All pertinent data to support this study are included in the paper and supplementary files. Further data supporting the findings are available upon request.

Competing interests

The authors declare no competing interests.

Funding information

This work was supported by The National Natural Science Foundation of China (NSFC, Nos. 81871952, 81670358 and 81873528), Six talent peaks project in Jiangsu Province (BU24600117), the project for the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) and National Center for International Research (2017B01012).

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Wu, C., Ding, H., Wang, S. et al. DAXX inhibits cancer stemness and epithelial–mesenchymal transition in gastric cancer. Br J Cancer (2020). https://doi.org/10.1038/s41416-020-0800-3

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