BET bromodomain inhibition blocks the function of a critical AR-independent master regulator network in lethal prostate cancer

被引：26

作者：

Coleman, Daniel J. ^{[1
]}

Gao, Lina ^{[1
]}

King, Carly J. ^{[1
,2
]}

Schwartzman, Jacob ^{[1
]}

Urrutia, Joshua ^{[1
]}

Sehrawat, Archana ^{[1
]}

Tayou, Junior ^{[1
]}

Balter, Ariel ^{[3
]}

Burchard, Julja ^{[3
]}

Chiotti, Kami E. ^{[1
,4
]}

Derrick, Daniel S. ^{[1
,2
]}

Sun, Duanchen ^{[2
]}

Xia, Zheng ^{[2
]}

Heiser, Laura M. ^{[1
,2
]}

Alumkal, Joshi J. ^{[1
,4
]}

机构：

[1] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97239 USA

[2] Oregon Hlth & Sci Univ, Dept Biomed Engn, Portland, OR 97239 USA

[3] Oregon Hlth & Sci Univ, Computat Biol Program, Portland, OR 97239 USA

[4] Oregon Hlth & Sci Univ, Dept Mol & Med Genet, Portland, OR 97239 USA

来源：

ONCOGENE | 2019年 / 38卷 / 28期

基金：

美国国家卫生研究院;

关键词：

CASTRATION-RESISTANT; ANDROGEN RECEPTOR; MCM PROTEINS; EXPRESSION; VARIANTS;

D O I：

10.1038/s41388-019-0815-5

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

BET bromodomain inhibitors block prostate cancer cell growth at least in part through c-Myc and androgen receptor (AR) suppression. However, little is known about other transcriptional regulators whose suppression contributes to BET bromodomain inhibitor anti-tumor activity. Moreover, the anti-tumor activity of BET bromodomain inhibition in AR-independent castration-resistant prostate cancers (CRPC), whose frequency is increasing, is also unknown. Herein, we demonstrate that BET bromodomain inhibition blocks growth of a diverse set of CRPC cell models, including those that are AR-independent or in which c-Myc is not suppressed. To identify transcriptional regulators whose suppression accounts for these effects, we treated multiple CRPC cell lines with the BET bromodomain inhibitor JQ1 and then performed RNA-sequencing followed by Master Regulator computational analysis. This approach identified several previously unappreciated transcriptional regulators that are highly expressed in CRPC and whose suppression, via both transcriptional or post-translational mechanisms, contributes to the anti-tumor activity of BET bromodomain inhibitors.

引用

页码：5658 / 5669

页数：12

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