Int J Biol Sci 2012; 8(8):1178-1187. doi:10.7150/ijbs.4458 This issue

Research Paper

DLX4 Upregulates TWIST and Enhances Tumor Migration, Invasion and Metastasis

Lianmei Zhang1*, Manman Yang1*, Lin Gan1, Tao He1, Xiuli Xiao1, M. David Stewart2, Xiaoyan Liu1, Luquan Yang1, Tiandan Zhang1, Yongxiang Zhao3✉, Junjiang Fu1✉

1. Key Laboratory of Epigenetics and Oncology, The Research Center for Preclinical Medicine, Luzhou Medical College, Luzhou, China 646000
2. Department of Biology & Biochemistry, University of Houston, Houston, TX, USA 77204
3. Biological Targeting Diagnosis and Therapy Research Center, Guangxi Medical University, Nanning, China 530021
* Co-first authors

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Zhang L, Yang M, Gan L, He T, Xiao X, Stewart MD, Liu X, Yang L, Zhang T, Zhao Y, Fu J. DLX4 Upregulates TWIST and Enhances Tumor Migration, Invasion and Metastasis. Int J Biol Sci 2012; 8(8):1178-1187. doi:10.7150/ijbs.4458. Available from

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The distal-less homeobox gene 4 (DLX4) is a member of the DLX family of homeobox genes. Although absent from most normal adult tissues, DLX4 is widely expressed in leukemia, lung, breast, ovarian and prostate cancers. However the molecular targets, mechanisms and pathways that mediate the role of DLX4 in tumor metastasis are poorly understood. In this study, we found that DLX4 induces cancer cells to undergo epithelial to mesenchymal transition (EMT) through TWIST. Overexpression of DLX4 increased expression of TWIST expression in cancer cell lines, resulting in increased migratory and invasive capacity. Likewise, knocking down expression of DLX4 decreased TWIST expression and the migration ability of cancer cell lines. DLX4 bound to regulatory regions of the TWIST gene. Both western blotting and immunohistochemistry staining showed that the expression of DLX4 and TWIST are correlated in most of breast tumors. Taken together, these data from both cell models and tumor tissues demonstrate that DLX4 not only upregulates TWIST expression but also induces EMT and tumor metastasis. Altogether, we propose a new pathway in which DLX4 drives expression of TWIST to promote EMT, cancer migration, invasion and metastasis.

Keywords: DLX4, TWIST, E-Cadherin, breast cancer, metastasis