TRIM24 Is an Oncogenic Transcriptional Activator in Prostate Cancer

被引：203

作者：

Groner, Anna C. ^{[1
,2
]}

Cato, Laura ^{[1
,2
]}

de Tribolet-Hardy, Jonas ^{[1
,2
]}

Bernasocchi, Tiziano ^{[3
]}

Janouskova, Hana ^{[3
]}

Melchers, Diana ^{[4
]}

Houtman, Rene ^{[4
]}

Cato, Andrew C. B. ^{[5
]}

Tschopp, Patrick ^{[6
]}

Gu, Lei ^{[7
,8
]}

Corsinotti, Andrea ^{[9
,10
]}

Zhong, Qing ^{[11
]}

Fankhauser, Christian ^{[11
,12
]}

Fritz, Christine ^{[11
]}

Poyet, Cedric ^{[12
]}

Wagner, Ulrich ^{[11
]}

Guo, Tiannan ^{[13
]}

Aebersold, Ruedi ^{[13
,14
]}

Garraway, Levi A. ^{[1
,15
,16
]}

Wild, Peter J. ^{[11
]}

Theurillat, Jean-Philippe ^{[3
,15
,17
]}

Brown, Myles ^{[1
,2
]}

机构：

[1] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Dana Farber Canc Inst, Ctr Funct Canc Epigenet, 44 Binney St, Boston, MA 02115 USA

[3] Inst Oncol Res, CH-6500 Bellinzona, Switzerland

[4] PamGene Int, NL-5211 HH Den Bosch, Netherlands

[5] Karlsruhe Inst Technol, Inst Toxicol & Genet, D-76344 Eggenstein Leopoldshafen, Germany

[6] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02215 USA

[7] Harvard Univ, Sch Med, Childrens Hosp Boston, Div Newborn Med, Boston, MA 02215 USA

[8] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02215 USA

[9] Univ Edinburgh, Sch Biol Sci, Inst Stem Cell Res, MRC Ctr Regenerat Med, Edinburgh EH16 4UU, Midlothian, Scotland

[10] Univ Tsukuba, Fac Med, Dept Anat & Embryol, Lab Anim Resource Ctr, 1-1-1 Tennodai, Tsukuba, Ibaraki 3058575, Japan

[11] Univ Zurich Hosp, Inst Surg Pathol, CH-8091 Zurich, Switzerland

[12] Univ Zurich Hosp, Dept Urol, CH-8091 Zurich, Switzerland

[13] ETH, Inst Mol Syst Biol, Dept Biol, CH-8093 Zurich, Switzerland

[14] Univ Zurich, Fac Sci, CH-8057 Zurich, Switzerland

[15] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA

[16] Harvard Univ, Sch Med, Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA

[17] Univ Lausanne, CHU Vaudois, CH-1011 Lausanne, Switzerland

来源：

CANCER CELL | 2016年 / 29卷 / 06期

基金：

瑞士国家科学基金会;

关键词：

ANDROGEN-RECEPTOR GENE; MUTATIONAL LANDSCAPE; SPOP; PROGRESSION; EXPRESSION; COACTIVATOR; RECURRENCE; MECHANISM; CELLS; MODEL;

D O I：

10.1016/j.ccell.2016.04.012

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Androgen receptor (AR) signaling is a key driver of prostate cancer (PC). While androgen-deprivation therapy is transiently effective in advanced disease, tumors often progress to a lethal castration-resistant state (CRPC). We show that recurrent PC-driver mutations in speckle-type POZ protein (SPOP) stabilize the TRIM24 protein, which promotes proliferation under low androgen conditions. TRIM24 augments AR signaling, and AR and TRIM24 co-activated genes are significantly upregulated in CRPC. Expression of TRIM24 protein increases from primary PC to CRPC, and both TRIM24 protein levels and the AR/TRIM24 gene signature predict disease recurrence. Analyses in CRPC cells reveal that the TRIM24 bromodomain and the AR-interacting motif are essential to support proliferation. These data provide a rationale for therapeutic TRIM24 targeting in SPOP mutant and CRPC patients.

引用

页码：846 / 858

页数：13

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