ONECUT2 acts as a lineage plasticity driver in adenocarcinoma as well as neuroendocrine variants of prostate cancer

被引：7

作者：

Qian, Chen ^{[1
]}

Yang, Qian ^{[2
,3
]}

Rotinen, Mirja ^{[4
]}

Huang, Rongrong ^{[5
]}

Kim, Hyoyoung ^{[2
,3
]}

Gallent, Brad ^{[1
,6
]}

Yan, Yiwu ^{[1
]}

Cadaneanu, Radu M. ^{[7
,8
]}

Zhang, Baohui ^{[7
,8
]}

Kaochar, Salma ^{[9
]}

Freedland, Stephen J. ^{[1
]}

Posadas, Edwin M. ^{[6
]}

Ellis, Leigh ^{[10
,11
,12
]}

Di Vizio, Dolores ^{[13
]}

Morrissey, Colm ^{[14
]}

Nelson, Peter S. ^{[15
,16
]}

Brady, Lauren ^{[15
,16
]}

Murali, Ramachandran ^{[1
]}

Campbell, Moray J. ^{[17
]}

Yang, Wei ^{[18
,19
]}

Knudsen, Beatrice S. ^{[20
,21
]}

Mostaghel, Elahe A. ^{[22
]}

Ye, Huihui ^{[23
]}

Garraway, Isla P. ^{[7
,8
]}

You, Sungyong ^{[2
,3
]}

Freeman, Michael R. ^{[1
]}

机构：

[1] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Dept Urol & Biomed Sci, Los Angeles, CA 90048 USA

[2] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Dept Urol, Los Angeles, CA 90048 USA

[3] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Dept Computat Biomed, Los Angeles, CA 90048 USA

[4] Univ Publ Navarra, Dept Hlth Sci, Navarra, Spain

[5] UCLA, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA

[6] Cedars Sinai Med Ctr, Dept Med, Div Med Oncol, Los Angeles, CA 90048 USA

[7] Univ Calif Los Angeles, David Geffen Sch Med, Jonsson Comprehens Canc Ctr, Box 951738,10833 Le Conte Ave 66-188 CHS UCLA, Los Angeles, CA 90095 USA

[8] Jonsson Comprehens Canc Ctr, David Geffen Sch Med, Dept Urol, 951738,10833 Conte Ave 66-188 CHS UCLA, Los Angeles, CA 90095 USA

[9] Baylor Coll Med, Dept Med, Sect Hematol Oncol, Houston, TX USA

[10] Uniformed Serv Univ Hlth Sci, Ctr Prostate Dis Res, Murtha Canc Ctr Res Program, Dept Surg, Bethesda, MD 20814 USA

[11] Walter Reed Natl Mil Med Ctr, Bethesda, MD 20814 USA

[12] NCI, Genitourinary Malignancies Branch, Ctr Canc Res, Bethesda, MD 20892 USA

[13] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Dept Urol Pathol & Lab Med, Los Angeles, CA 90048 USA

[14] Univ Washington, Dept Urol, Seattle, WA 98195 USA

[15] Fred Hutchinson Canc Ctr, Div Human Biol, Seattle, WA 98109 USA

[16] Fred Hutchinson Canc Ctr, Div Clin Res, Seattle, WA 98109 USA

[17] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Los Angeles, CA 90048 USA

[18] SUNY Stony Brook, Dept Pathol, Stony Brook, NY 11794 USA

[19] SUNY Stony Brook, Canc Ctr, Stony Brook, NY 11794 USA

[20] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT 84108 USA

[21] Univ Utah, Dept Pathol, Salt Lake City, UT 84108 USA

[22] US Dept Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr GRECC, Seattle, WA 98133 USA

[23] Cedars Sinai Med Ctr, Dept Pathol, Los Angeles, CA 90048 USA

来源：

NUCLEIC ACIDS RESEARCH | 2024年 / 52卷 / 13期

关键词：

DNA-POLYMERASE GAMMA; MITOCHONDRIAL LON PROTEASE; FUNCTIONAL-CHARACTERIZATION; GLUCOCORTICOID-RECEPTOR; TRANSCRIPTION FACTORS; CATALYTIC SUBUNIT; ACCESSORY SUBUNIT; STRUCTURAL BASIS; POLG2; MUTATIONS;

D O I：

10.1093/nar/gkae547

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Androgen receptor- (AR-) indifference is a mechanism of resistance to hormonal therapy in prostate cancer (PC). Here we demonstrate that ONECUT2 (OC2) activates resistance through multiple drivers associated with adenocarcinoma, stem-like and neuroendocrine (NE) variants. Direct OC2 gene targets include the glucocorticoid receptor (GR; NR3C1) and the NE splicing factor SRRM4, which are key drivers of lineage plasticity. Thus, OC2, despite its previously described NEPC driver function, can indirectly activate a portion of the AR cistrome through epigenetic activation of GR. Mechanisms by which OC2 regulates gene expression include promoter binding, enhancement of genome-wide chromatin accessibility, and super-enhancer reprogramming. Pharmacologic inhibition of OC2 suppresses lineage plasticity reprogramming induced by the AR signaling inhibitor enzalutamide. These results demonstrate that OC2 activation promotes a range of drug resistance mechanisms associated with treatment-emergent lineage variation in PC and support enhanced efforts to therapeutically target OC2 as a means of suppressing treatment-resistant disease. Graphical Abstract

引用

页码：7740 / 7760

页数：21

共 1 条

[1] ONECUT2 is a targetable master regulator of lethal prostate cancer that suppresses the androgen axis
Rotinen, Mirja
You, Sungyong
Yang, Julie
Coetzee, Simon G.
Reis-Sobreiro, Mariana
Huang, Wen-Chin
Huang, Fangjin
Pan, Xinlei
Yanez, Alberto
Hazelett, Dennis J.
Chu, Chia-Yi
Steadman, Kenneth
Morrissey, Colm M.
Nelson, Peter S.
Corey, Eva
Chung, Leland W. K.
Freedland, Stephen J.
Di Vizio, Dolores
Garraway, Isla P.
Murali, Ramachandran
Knudsen, Beatrice S.
Freeman, Michael R.
NATURE MEDICINE, 2018, 24 (12) : 1887 - +

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