CUL4A induces epithelial-mesenchymal transition and promotes cancer metastasis by regulating ZEB1 expression

Yunshan Wang, Mingxin Wen, Yongwon Kwon, Yangyang Xu, Yueyong Liu, Pengju Zhang, Xiuquan He, Qin Wang, Yurong Huang, Kuang-Yu Jen, Mark A. Labarge, Liang You, Scott C. Kogan, Joe W. Gray, Jian Hua Mao, Guangwei Wei

Research output: Contribution to journalArticle

140 Scopus citations

Abstract

The ubiquitin ligase CUL4A has been implicated in tumorigenesis, but its contributions to progression and metastasis have not been evaluated. Here, we show that CUL4A is elevated in breast cancer as well as in ovarian, gastric, and colorectal tumors in which its expression level correlates positively with distant metastasis. CUL4A overexpression in normal or malignant human mammary epithelial cells increased their neoplastic properties in vitro and in vivo, markedly increasing epithelial-mesenchymal transition (EMT) and the metastatic capacity of malignant cells. In contrast, silencing CUL4A in aggressive breast cancer cells inhibited these processes. Mechanistically, we found that CUL4A modulated histone H3K4me3 at the promoter of the EMT regulatory gene ZEB1 in a manner associated with its transcription. ZEB1 silencing blocked CUL4A-driven proliferation, EMT, tumorigenesis, and metastasis. Furthermore, in human breast cancers, ZEB1 expression correlated positively with CUL4A expression and distant metastasis. Taken together, our findings reveal a pivotal role of CUL4A in regulating the metastatic behavior of breast cancer cells.

Original languageEnglish (US)
Pages (from-to)520-531
Number of pages12
JournalCancer Research
Volume74
Issue number2
DOIs
StatePublished - Jan 15 2014
Externally publishedYes

    Fingerprint

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Wang, Y., Wen, M., Kwon, Y., Xu, Y., Liu, Y., Zhang, P., He, X., Wang, Q., Huang, Y., Jen, K-Y., Labarge, M. A., You, L., Kogan, S. C., Gray, J. W., Mao, J. H., & Wei, G. (2014). CUL4A induces epithelial-mesenchymal transition and promotes cancer metastasis by regulating ZEB1 expression. Cancer Research, 74(2), 520-531. https://doi.org/10.1158/0008-5472.CAN-13-2182