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Regulation of p21 by TWIST2 contributes to its tumor-suppressor function in human acute myeloid leukemia

Oncogene volume 34, pages 3000–3010 (2015)Cite this article

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Abstract

TWIST2 has a dual function in tumors. Its implication in the initiation and metastasis of various solid tumors is well established, and its tumor-suppressor role in murine osteosarcoma cells has been reported recently. However, the function of TWIST2 and its underlying mechanisms in human normal and malignant hematopoiesis remain unclear. In the present study, we found that TWIST2 directly regulated p21 in human hematopoietic cells and whose silence promoted cell proliferation and cell cycle progression. Hypermethylation of TWIST2 occurred to 23 out of the 75 adult acute myeloid leukemia (AML) patients and resulted in the impaired expression of both TWIST2 and p21. Conversely, TWIST2 overexpression inhibited the growth of AML cells partially through its direct activation of p21 with intact HLH (helix-loop-helix) domain. The microarray data and gene expression validation showed that TWIST2 was sufficient to activate known tumor-suppressor genes, whereas suppress known oncogenes, which further supported its inhibitory effect against AML cells. Taken together, our data have identified a novel TWIST2-p21 axis that modulates the cell cycle of both normal and leukemic cells and demonstrated that the direct regulation of p21 by TWIST2 has a role in its tumor-suppressor function in AML.

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Acknowledgements

This work was funded by National Natural Science Foundation of China (no. 31170755), National Key Scientific Project of China (973 Program no. 2011CB933501), Specialized Research Fund for the Doctoral Program of Higher Education (SRFDP, no. 20113201120017), the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), Jiangsu Province’s Key Medical Center (ZX201102) and National Public Health Grand Research Foundation (No.201202017).

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Author notes

  1. J Cui

    Present address: 7Current address: Shanxi Academy of Medical Science, Shanxi Da Yi Hospital, Taiyuan, Shanxi 030032, People's Republic of China.,

  2. X Zhang, W Ma and J Cui: These authors contributed equally to this work.

  3. D Wu and Y Zhao: These two authors are co-senior authors.

Authors and Affiliations

  1. Cyrus Tang Hematology Center, Soochow University, Suzhou, People's Republic of China,

    X Zhang, W Ma, J Cui, H Yao, Y Ge, L Xiao & Y Zhao

  2. Collaborative Innovation Center of Hematology, Soochow University, Suzhou, People's Republic of China,

    X Zhang, W Ma, S Chen, D Wu & Y Zhao

  3. The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis, Suzhou, People's Republic of China

    J Cui, H Yao, H Zhou, X Hu, S Chen & D Wu

  4. Shanghai Center for Bioinformation Technology, Shanghai, People's Republic of China

    B-H Liu, J Yang & Y-Y Li

  5. Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada

    C J Eaves

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Zhang, X., Ma, W., Cui, J. et al. Regulation of p21 by TWIST2 contributes to its tumor-suppressor function in human acute myeloid leukemia. Oncogene 34, 3000–3010 (2015). https://doi.org/10.1038/onc.2014.241

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