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 Gray, Jian Hua Mao, Guangwei Wei

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139 Citations (Scopus)

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

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Epithelial-Mesenchymal Transition
Breast Neoplasms
Neoplasm Metastasis
Neoplasms
Carcinogenesis
Regulator Genes
Ligases
Ubiquitin
Histones
Colorectal Neoplasms
Stomach
Breast
Epithelial Cells

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

CUL4A induces epithelial-mesenchymal transition and promotes cancer metastasis by regulating ZEB1 expression. / Wang, Yunshan; Wen, Mingxin; Kwon, Yongwon; Xu, Yangyang; Liu, Yueyong; Zhang, Pengju; He, Xiuquan; Wang, Qin; Huang, Yurong; Jen, Kuang Yu; Labarge, Mark A.; You, Liang; Kogan, Scott C.; Gray, Joe; Mao, Jian Hua; Wei, Guangwei.

In: Cancer Research, Vol. 74, No. 2, 15.01.2014, p. 520-531.

Research output: Contribution to journalArticle

Wang, Y, Wen, M, Kwon, Y, Xu, Y, Liu, Y, Zhang, P, He, X, Wang, Q, Huang, Y, Jen, KY, Labarge, MA, You, L, Kogan, SC, Gray, J, Mao, JH & Wei, G 2014, 'CUL4A induces epithelial-mesenchymal transition and promotes cancer metastasis by regulating ZEB1 expression', Cancer Research, vol. 74, no. 2, pp. 520-531. https://doi.org/10.1158/0008-5472.CAN-13-2182
Wang, Yunshan ; Wen, Mingxin ; Kwon, Yongwon ; Xu, Yangyang ; Liu, Yueyong ; Zhang, Pengju ; He, Xiuquan ; Wang, Qin ; Huang, Yurong ; Jen, Kuang Yu ; Labarge, Mark A. ; You, Liang ; Kogan, Scott C. ; Gray, Joe ; Mao, Jian Hua ; Wei, Guangwei. / CUL4A induces epithelial-mesenchymal transition and promotes cancer metastasis by regulating ZEB1 expression. In: Cancer Research. 2014 ; Vol. 74, No. 2. pp. 520-531.
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