EZH2 inhibition suppresses endometrial cancer progression via miR-361/Twist axis.

Kei Ihira; Peixin Dong; Ying Xiong; Hidemichi Watari; Yosuke Konno; Sharon J. B. Hanley; Masayuki Noguchi; Noriyuki Hirata; Futoshi Suizu; Takahiro Yamada; Masataka Kudo; Noriaki Sakuragi

doi:10.18632/oncotarget.14586

EZH2 inhibition suppresses endometrial cancer progression via miR-361/Twist axis.

Kei Ihira, Peixin Dong^* (Corresponding Author), Ying Xiong, Hidemichi Watari^* (Corresponding Author), Yosuke Konno, Sharon J. B. Hanley, Masayuki Noguchi, Noriyuki Hirata, Futoshi Suizu, Takahiro Yamada, Masataka Kudo, Noriaki Sakuragi^* (Corresponding Author)

^*Corresponding author for this work

Applied Health Sciences

Research output: Contribution to journal › Article › peer-review

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Abstract

EZH2 inhibition and reactivation of tumor suppressor microRNAs (miRNAs) represent attractive anti-cancer therapeutic strategies. We found that EZH2-suppressed let 7b and miR-361, two likely tumor suppressors, inhibited endometrial cancer (EC) cell proliferation and invasion, and abrogated cancer stem cell-like properties. In EC cells, EZH2 induced and functioned together with YY1 to epigenetically suppress miR-361, which upregulated Twist, a direct target of miR-361. Treating EC cells with GSK343, a specific EZH2 inhibitor, mimicked the effects of siRNA-mediated EZH2 knockdown, upregulating miR-361 and downregulating Twist expression. Combining GSK343 with 5 AZA-2'-deoxycytidine synergistically suppressed cell proliferation and invasion in vitro, and decreased tumor size and weight in EC cell xenografted mice. Quantitative real-time PCR analysis of 24 primary EC tissues showed that lower let-7b and miR-361 levels were associated with worse patient outcomes. These results were validated in a larger EC patient dataset from The Cancer Genome Atlas. Our findings suggest that EZH2 drives EC progression by regulating miR-361/Twist signaling, and support EZH2 inhibition as a promising anti-EC therapeutic strategy.

Original language	English
Pages (from-to)	13509-13520
Number of pages	12
Journal	Oncotarget
Volume	8
Issue number	8
Early online date	10 Jan 2017
DOIs	https://doi.org/10.18632/oncotarget.14586
Publication status	Published - 10 Jan 2017

Bibliographical note

ACKNOWLEDGMENTS
We thank Dr. Zhujie Xu for experimental assistance.

GRANT SUPPORT
This work was funded by a grant from the Department of Women’s Health Educational System, a Grant-in-Aid for Scientific Research (C) (15K10697
and 16K11123) and by the Science and Technology Planning Project of Guangdong Province, China (2013B021800155).

Keywords

5-AZA-CdR
endometrial cancer
EZH2
GSK343
miR-361

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Cite this

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title = "EZH2 inhibition suppresses endometrial cancer progression via miR-361/Twist axis.",

abstract = "EZH2 inhibition and reactivation of tumor suppressor microRNAs (miRNAs) represent attractive anti-cancer therapeutic strategies. We found that EZH2-suppressed let 7b and miR-361, two likely tumor suppressors, inhibited endometrial cancer (EC) cell proliferation and invasion, and abrogated cancer stem cell-like properties. In EC cells, EZH2 induced and functioned together with YY1 to epigenetically suppress miR-361, which upregulated Twist, a direct target of miR-361. Treating EC cells with GSK343, a specific EZH2 inhibitor, mimicked the effects of siRNA-mediated EZH2 knockdown, upregulating miR-361 and downregulating Twist expression. Combining GSK343 with 5 AZA-2'-deoxycytidine synergistically suppressed cell proliferation and invasion in vitro, and decreased tumor size and weight in EC cell xenografted mice. Quantitative real-time PCR analysis of 24 primary EC tissues showed that lower let-7b and miR-361 levels were associated with worse patient outcomes. These results were validated in a larger EC patient dataset from The Cancer Genome Atlas. Our findings suggest that EZH2 drives EC progression by regulating miR-361/Twist signaling, and support EZH2 inhibition as a promising anti-EC therapeutic strategy.",

keywords = "5-AZA-CdR, endometrial cancer, EZH2, GSK343, miR-361",

author = "Kei Ihira and Peixin Dong and Ying Xiong and Hidemichi Watari and Yosuke Konno and Hanley, {Sharon J. B.} and Masayuki Noguchi and Noriyuki Hirata and Futoshi Suizu and Takahiro Yamada and Masataka Kudo and Noriaki Sakuragi",

note = "ACKNOWLEDGMENTS We thank Dr. Zhujie Xu for experimental assistance. GRANT SUPPORT This work was funded by a grant from the Department of Women{\textquoteright}s Health Educational System, a Grant-in-Aid for Scientific Research (C) (15K10697 and 16K11123) and by the Science and Technology Planning Project of Guangdong Province, China (2013B021800155). ",

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AU - Ihira, Kei

AU - Dong, Peixin

AU - Xiong, Ying

AU - Watari, Hidemichi

AU - Konno, Yosuke

AU - Hanley, Sharon J. B.

AU - Noguchi, Masayuki

AU - Hirata, Noriyuki

AU - Suizu, Futoshi

AU - Yamada, Takahiro

AU - Kudo, Masataka

AU - Sakuragi, Noriaki

N1 - ACKNOWLEDGMENTS We thank Dr. Zhujie Xu for experimental assistance. GRANT SUPPORT This work was funded by a grant from the Department of Women’s Health Educational System, a Grant-in-Aid for Scientific Research (C) (15K10697 and 16K11123) and by the Science and Technology Planning Project of Guangdong Province, China (2013B021800155).

PY - 2017/1/10

Y1 - 2017/1/10

N2 - EZH2 inhibition and reactivation of tumor suppressor microRNAs (miRNAs) represent attractive anti-cancer therapeutic strategies. We found that EZH2-suppressed let 7b and miR-361, two likely tumor suppressors, inhibited endometrial cancer (EC) cell proliferation and invasion, and abrogated cancer stem cell-like properties. In EC cells, EZH2 induced and functioned together with YY1 to epigenetically suppress miR-361, which upregulated Twist, a direct target of miR-361. Treating EC cells with GSK343, a specific EZH2 inhibitor, mimicked the effects of siRNA-mediated EZH2 knockdown, upregulating miR-361 and downregulating Twist expression. Combining GSK343 with 5 AZA-2'-deoxycytidine synergistically suppressed cell proliferation and invasion in vitro, and decreased tumor size and weight in EC cell xenografted mice. Quantitative real-time PCR analysis of 24 primary EC tissues showed that lower let-7b and miR-361 levels were associated with worse patient outcomes. These results were validated in a larger EC patient dataset from The Cancer Genome Atlas. Our findings suggest that EZH2 drives EC progression by regulating miR-361/Twist signaling, and support EZH2 inhibition as a promising anti-EC therapeutic strategy.

AB - EZH2 inhibition and reactivation of tumor suppressor microRNAs (miRNAs) represent attractive anti-cancer therapeutic strategies. We found that EZH2-suppressed let 7b and miR-361, two likely tumor suppressors, inhibited endometrial cancer (EC) cell proliferation and invasion, and abrogated cancer stem cell-like properties. In EC cells, EZH2 induced and functioned together with YY1 to epigenetically suppress miR-361, which upregulated Twist, a direct target of miR-361. Treating EC cells with GSK343, a specific EZH2 inhibitor, mimicked the effects of siRNA-mediated EZH2 knockdown, upregulating miR-361 and downregulating Twist expression. Combining GSK343 with 5 AZA-2'-deoxycytidine synergistically suppressed cell proliferation and invasion in vitro, and decreased tumor size and weight in EC cell xenografted mice. Quantitative real-time PCR analysis of 24 primary EC tissues showed that lower let-7b and miR-361 levels were associated with worse patient outcomes. These results were validated in a larger EC patient dataset from The Cancer Genome Atlas. Our findings suggest that EZH2 drives EC progression by regulating miR-361/Twist signaling, and support EZH2 inhibition as a promising anti-EC therapeutic strategy.

KW - 5-AZA-CdR

KW - endometrial cancer

KW - EZH2

KW - GSK343

KW - miR-361

U2 - 10.18632/oncotarget.14586

DO - 10.18632/oncotarget.14586

M3 - Article

SN - 1949-2553

VL - 8

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JO - Oncotarget

JF - Oncotarget

IS - 8

ER -

EZH2 inhibition suppresses endometrial cancer progression via miR-361/Twist axis.

Abstract

Bibliographical note

Keywords

UN SDGs

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