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Int J Mol Sci. 2018 Jul 20;19(7). pii: E2104. doi: 10.3390/ijms19072104.

BRCA1 Interacting Protein COBRA1 Facilitates Adaptation to Castrate-Resistant Growth Conditions.

Yun H1,2, Bedolla R3, Horning A4, Li R5,6, Chiang HC7, Huang TH8,9, Reddick R10, Olumi AF11, Ghosh R12,13,14,15, Kumar AP16,17,18,19,20.

Author information

1
Department of Urology, The University of Texas Health, San Antonio, TX 78229, USA. Huiyoung_Yun@DFCI.HARVARD.EDU.
2
Pharmacology, the University of Texas Health, San Antonio, TX 78229, USA. Huiyoung_Yun@DFCI.HARVARD.EDU.
3
Department of Urology, The University of Texas Health, San Antonio, TX 78229, USA. BEDOLLAR@uthscsa.edu.
4
Molecular Medicine, The University of Texas Health, San Antonio, TX 78229, USA. Horning@livemail.uthscsa.edu.
5
Molecular Medicine, The University of Texas Health, San Antonio, TX 78229, USA. lir3@uthscsa.edu.
6
UT Health San Antonio Cancer Center, the University of Texas Health, San Antonio, TX 78229, USA. lir3@uthscsa.edu.
7
Molecular Medicine, The University of Texas Health, San Antonio, TX 78229, USA. chiangh@uthscsa.edu.
8
Molecular Medicine, The University of Texas Health, San Antonio, TX 78229, USA. huangt3@uthscsa.edu.
9
UT Health San Antonio Cancer Center, the University of Texas Health, San Antonio, TX 78229, USA. huangt3@uthscsa.edu.
10
Pathology, the University of Texas Health, San Antonio, TX 78229, USA. REDDICK@uthscsa.edu.
11
Department of Urology, Massachusetts General Hospital Harvard Medical School, 55 Fruit Street, Yawkey Building, Suite 7E, Boston, MA 02215, USA. AOLUMI@PARTNERS.ORG.
12
Department of Urology, The University of Texas Health, San Antonio, TX 78229, USA. ghoshr@uthscsa.edu.
13
Pharmacology, the University of Texas Health, San Antonio, TX 78229, USA. ghoshr@uthscsa.edu.
14
Molecular Medicine, The University of Texas Health, San Antonio, TX 78229, USA. ghoshr@uthscsa.edu.
15
UT Health San Antonio Cancer Center, the University of Texas Health, San Antonio, TX 78229, USA. ghoshr@uthscsa.edu.
16
Department of Urology, The University of Texas Health, San Antonio, TX 78229, USA. kumara3@uthscsa.edu.
17
Pharmacology, the University of Texas Health, San Antonio, TX 78229, USA. kumara3@uthscsa.edu.
18
Molecular Medicine, The University of Texas Health, San Antonio, TX 78229, USA. kumara3@uthscsa.edu.
19
UT Health San Antonio Cancer Center, the University of Texas Health, San Antonio, TX 78229, USA. kumara3@uthscsa.edu.
20
South Texas Veterans Health Care System, San Antonio, TX 78229, USA. kumara3@uthscsa.edu.

Abstract

COBRA1 (co-factor of BRCA1) is one of the four subunits of the negative elongation factor originally identified as a BRCA1-interacting protein. Here, we provide first-time evidence for the oncogenic role of COBRA1 in prostate pathogenesis. COBRA1 is aberrantly expressed in prostate tumors. It positively influences androgen receptor (AR) target gene expression and promoter activity. Depletion of COBRA1 leads to decreased cell viability, proliferation, and anchorage-independent growth in prostate cancer cell lines. Conversely, overexpression of COBRA1 significantly increases cell viability, proliferation, and anchorage-independent growth over the higher basal levels. Remarkably, AR-positive androgen dependent (LNCaP) cells overexpressing COBRA1 survive under androgen-deprivation conditions. Remarkably, treatment of prostate cancer cells with well-studied antitumorigenic agent, 2-methoxyestradiol (2-ME₂), caused significant DNA methylation changes in 3255 genes including COBRA1. Furthermore, treatment of prostate cancer cells with 2-ME₂ downregulates COBRA1 and inhibition of prostate tumors in TRAMP (transgenic adenocarcinomas of mouse prostate) animals with 2-ME₂ was also associated with decreased COBRA1 levels. These observations implicate a novel role for COBRA1 in progression to CRPC and suggest that COBRA1 downregulation has therapeutic potential.

KEYWORDS:

COBRA1; CRPC; NELFB; androgen receptor

PMID:
30036938
PMCID:
PMC6073349
DOI:
10.3390/ijms19072104
[Indexed for MEDLINE]
Free PMC Article

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