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2016 ; 11
(3
): e0151598
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CYP1B1 Enhances Cell Proliferation and Metastasis through Induction of EMT and
Activation of Wnt/?-Catenin Signaling via Sp1 Upregulation
#MMPMID26981862
Kwon YJ
; Baek HS
; Ye DJ
; Shin S
; Kim D
; Chun YJ
PLoS One
2016[]; 11
(3
): e0151598
PMID26981862
show ga
Cytochrome P450 1B1 (CYP1B1) is a major E2 hydroxylase involved in the metabolism
of potential carcinogens. CYP1B1 expression has been reported to be higher in
tumors compared to normal tissues, especially in hormone-related cancers
including breast, ovary, and prostate tumors. To explore the role of CYP1B1 in
cancer progression, we investigated the action of CYP1B1 in cells with increased
CYP1B1 via the inducer 7,12-dimethylbenz[?]anthracene (DMBA) or an overexpression
vector, in addition to decreased CYP1B1 via the inhibitor tetramethoxystilbene
(TMS) or siRNA knockdown. We observed that CYP1B1 promoted cell proliferation,
migration, and invasion in MCF-7 and MCF-10A cells. To understand its molecular
mechanism, we measured key oncogenic proteins including ?-catenin, c-Myc, ZEB2,
and matrix metalloproteinases following CYP1B1 modulation. CYP1B1 induced
epithelial-mesenchymal transition (EMT) and activated Wnt/?-catenin signaling via
upregulation of CTNNB1, ZEB2, SNAI1, and TWIST1. Sp1, a transcription factor
involved in cell growth and metastasis, was positively regulated by CYP1B1, and
suppression of Sp1 expression by siRNA or DNA binding activity using mithramycin
A blocked oncogenic transformation by CYP1B1. Therefore, we suggest that Sp1 acts
as a key mediator for CYP1B1 action. Treatment with 4-hydroxyestradiol (4-OHE2),
a major metabolite generated by CYP1B1, showed similar effects as CYP1B1
overexpression, indicating that CYP1B1 activity mediated various oncogenic events
in cells. In conclusion, our data suggests that CYP1B1 promotes cell
proliferation and metastasis by inducing EMT and Wnt/?-catenin signaling via Sp1
induction.