EURURO Vol. 72 No. 5

Prostate Cancer

Preclinical Study using

Malat1

Small Interfering RNA or Androgen

Receptor Splicing Variant 7 Degradation Enhancer ASC-J9

[8_TD$DIFF]

Suppress Enzalutamide-resistant Prostate Cancer Progression

Ronghao Wang

a , 1

, Yin Sun

a , 1

, Lei Li

a , b , *

[10_TD$DIFF]

, Yuanjie Niu

a , d

[11_TD$DIFF]

, Wanying Lin

, Changyi Lin

Emmanuel S. Antonarakis

, Jun Luo

, Shuyuan Yeh

, Chawnshang Chang

a , d , e , *

George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester

Medical Center, Rochester, NY, USA;

Chawnshang Chang Sex Hormone Research Center, Department of Urology, The First Affiliated Hospital, Xi’an Jiaotong

University, Xi’an, China;

Prostate Cancer Program, Sidney Kimmel Comprehensive Cancer Center, and James Buchannan Brady Department of Urology, Johns

Hopkins University School of Medicine, Baltimore, MD, USA;

Chawnshang Chang Sex Hormone Research Center,

[13_TD$DIFF]

Tianjin

[14_TD$DIFF]

Institute

[15_TD$DIFF]

[16_TD$DIFF]

Urology,

[17_TD$DIFF]

Tianjin

[18_TD$DIFF]

Medical

[19_TD$DIFF]

University,

[20_TD$DIFF]

Tianjin, China;

Sex Hormone Research

[23_TD$DIFF]

Center,

[24_TD$DIFF]

China Medical University

[25_TD$DIFF]

/Hospital,

[26_TD$DIFF]

Taichung,

[27_TD$DIFF]

Taiwan

E U R O P E A N U R O L O G Y 7 2 ( 2 0 1 7 ) 8 3 5 – 8 4 4

ava ilable at

www.sciencedirect.com

journal homepage:

www.eu ropeanurology.com

Article info

Article history:

Accepted April 4, 2017

Associate Editor:

James Catto

Keywords:

PCa

AR-v7

Malat1

Enzalutamide

Abstract

Background:

While androgen-deprivation-therapy with the recently developed anti-

androgen enzalutamide (Enz) shows promising therapeutic benefits in men with

metastatic castration-resistant prostate cancer (PCa), many patients develop resistance

to Enz, which may involve the induction of the androgen receptor (AR) splicing variant 7

(AR-v7).

Objective:

Our aim is to identify the mechanisms responsible for AR-v7 production and

to develop novel preclinical approaches to suppress the Enz-resistant (EnzR) PCa.

Design, setting, and participants:

We established EnzR-PCa cell lines and examined the

long noncoding RNA

Malat1

(

Malat1

) function in conferring Enz resistance. We also

examined the in vivo effects of

Malat1

short interfering

RNA

and the AR-v7 degradation

enhancer, ASC-J9

[12_TD$DIFF]

Outcome measurements and statistical analysis:

Enz resistance and expression of

Malat1

and AR-v7. All statistical comparisons were analyzed with a

test or one way

analysis of variance followed by

test.

Results and limitations:

We demonstrated that

Malat1

is indispensable for Enz-induced

AR-v7 production in VCaP and EnzR-C4-2 cells. We observed increased AR-v7 and

Malat1

expression in our established EnzR-PCa cell lines and in some PCa patients who received

Enz treatment. Targeting the

Malat1

/AR-v7 axis resulted in altering the PCa resistance to

androgen deprivation therapy with Enz. The limitation of this study includes the small

sample size from the same human patients before and after receiving Enz treatment.

Conclusions:

Targeting the

Malat1

/AR-v7 axis

via Malat1

-short interfering RNA or AR-v7

degradation enhancer ASC-J9

in EnzR-PCa cell lines and mouse models suppressed

EnzR-PCa progression.

Patient summary:

Androgen deprivation therapy-enzalutamide treatment may not be

the best choice for prostate cancer patients who have higher expression of the

Malat1

androgen receptor splicing variant 7 axis, and new therapies using

Malat1

-short

interfering RNA or ASC-J9

may be developed in the future to better suppress enza-

lutamide-resistant prostate cancer.

[3_TD$DIFF]

These authors contributed equally to this work.

* Corresponding

[34_TD$DIFF]

authors.

E-mail addresses:

lilydr@163.com

(L. Li),

chang@urmc.rochester.edu

(C. Chang).

http://dx.doi.org/10.1016/j.eururo.2017.04.005

0302-2838/