Regulation of p21 by TWIST2 contributes to its tumor-suppressor function in human acute myeloid leukemia
Regulation of p21 by TWIST2 contributes to its tumor-suppressor function in human acute myeloid leukemia
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DOI：
10.1038/onc.2014.241
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发表时间：
2014-08
期刊：
影响因子：
8
通讯作者：
Xueguang Zhang;W. Ma;J. Cui;H. Yao;Haixia Zhou;Y. Ge;L. Xiao;X. Hu;Liu Bh;J. Yang;Li Yy;S. Chen;Connie J. Eaves;D. Wu;Yun Zhao
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作者：
Xueguang Zhang;W. Ma;J. Cui;H. Yao;Haixia Zhou;Y. Ge;L. Xiao;X. Hu;Liu Bh;J. Yang;Li Yy;S. Chen;Connie J. Eaves;D. Wu;Yun Zhao
TWIST 2在肿瘤中具有双重功能。它在各种实体瘤的发生和转移中的作用已经得到了很好的证实，并且最近已经报道了它在小鼠骨肉瘤细胞中的肿瘤抑制作用。然而，TWIST 2的功能及其在人类正常和恶性造血中的潜在机制仍不清楚。在本研究中，我们发现TWIST 2直接调节人造血细胞中的p21，并且其沉默促进细胞增殖和细胞周期进展。在75例成人急性髓细胞白血病（AML）患者中，23例发生了TWIST 2的高甲基化，并导致TWIST 2和p21的表达受损。相反，TWIST 2过表达抑制AML细胞的生长，部分是通过其直接激活具有完整HLH（螺旋-环-螺旋）结构域的p21。微阵列数据和基因表达验证表明，TWIST 2足以激活已知的肿瘤抑制基因，而抑制已知的癌基因，这进一步支持了其对AML细胞的抑制作用。总之，我们的数据已经确定了一种新的TWIST 2-p21轴，它调节正常和白血病细胞的细胞周期，并证明TWIST 2对p21的直接调节在AML的肿瘤抑制功能中发挥作用。
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.