TY - JOUR
T1 - CUL4A induces epithelial-mesenchymal transition and promotes cancer metastasis by regulating ZEB1 expression
AU - Wang, Yunshan
AU - Wen, Mingxin
AU - Kwon, Yongwon
AU - Xu, Yangyang
AU - Liu, Yueyong
AU - Zhang, Pengju
AU - He, Xiuquan
AU - Wang, Qin
AU - Huang, Yurong
AU - Jen, Kuang Yu
AU - Labarge, Mark A.
AU - You, Liang
AU - Kogan, Scott C.
AU - Gray, Joe W.
AU - Mao, Jian Hua
AU - Wei, Guangwei
PY - 2014/1/15
Y1 - 2014/1/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84892934487&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84892934487&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-13-2182
DO - 10.1158/0008-5472.CAN-13-2182
M3 - Article
C2 - 24305877
AN - SCOPUS:84892934487
SN - 0008-5472
VL - 74
SP - 520
EP - 531
JO - Cancer Research
JF - Cancer Research
IS - 2
ER -