Regulation of tumor angiogenesis by EZH2.
Although VEGF-targeted therapies are showing promise, new angiogenesis targets are needed to make additional gains. Here, we show that increased Zeste homolog 2 (EZH2) expression in either tumor cells or in tumor vasculature is predictive of poor clinical outcome. The increase in endothelial EZH2 is a direct result of VEGF stimulation by a paracrine circuit that promotes angiogenesis by methylating and silencing vasohibin1 (vash1). Ezh2 silencing in the tumor-associated endothelial cells inhibited angiogenesis mediated by reactivation of VASH1, and reduced ovarian cancer growth, which is further enhanced in combination with ezh2 silencing in tumor cells. Collectively, these data support the potential for targeting ezh2 as an important therapeutic approach.
Lu
Chunhua
C
Department of Gynecologic Oncology, U.T. M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Han
Hee Dong
HD
Mangala
Lingegowda S
LS
Ali-Fehmi
Rouba
R
Newton
Christopher S
CS
Ozbun
Laurent
L
Armaiz-Pena
Guillermo N
GN
Hu
Wei
W
Stone
Rebecca L
RL
Munkarah
Adnan
A
Ravoori
Murali K
MK
Shahzad
Mian M K
MM
Lee
Jeong-Won
JW
Mora
Edna
E
Langley
Robert R
RR
Carroll
Amy R
AR
Matsuo
Koji
K
Spannuth
Whitney A
WA
Schmandt
Rosemarie
R
Jennings
Nicholas B
NB
Goodman
Blake W
BW
Jaffe
Robert B
RB
Nick
Alpa M
AM
Kim
Hye Sun
HS
Guven
Eylem Ozturk
EO
Chen
Ya-Huey
YH
Li
Long-Yuan
LY
Hsu
Ming-Chuan
MC
Coleman
Robert L
RL
Calin
George A
GA
Denkbas
Emir B
EB
Lim
Jae Yun
JY
Lee
Ju-Seog
JS
Kundra
Vikas
V
Birrer
Michael J
MJ
Hung
Mien-Chie
MC
Lopez-Berestein
Gabriel
G
Sood
Anil K
AK
D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019175:DNA Methylation; D017931:DNA Primers; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D020868:Gene Silencing; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000502:physiology*; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D010051:Ovarian Neoplasms / Q000098:blood supply* / Q000473:pathology; D063151:Polycomb Repressive Complex 2
D017931:DNA Primers; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2