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

Hokkaido University
Sun Yat-Sen University

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

74 Citations (Scopus)

9 Downloads (Pure)

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).

UN SDGs

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

SDG 3 Good Health and Well-being

Keywords

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

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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

UN SDGs

Keywords

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