Am J Cancer Res 2012;2(5):540-548
Original Article
BRCA1 proteins regulate growth of ovarian cancer cells by tethering Ubc9
Yunlong Qin, Jingyao Xu, Kartik Aysola, Gabriela Oprea, Avinash Reddy, Roland Matthews, Joel Okoli, Alan Cantor, William E
Grizzle, Edward E Partridge, E Shyam P Reddy, Charles Landen, Veena N Rao
Cancer Biology Program, Department of OB/GYN; Department of Surgery Morehouse School of Medicine, Georgia Cancer Center
for Excellence, Grady Health System, Atlanta, GA 30303, USA; Department of Pathology, University of Alabama at Birmingham,
703 19th Street South, Birmingham, AL 35294-0007, USA; Department of Obstetrics & Gynecology, Division of Gynecological
Oncology, 618 20th Street South, University of Alabama at Birmingham, Birmingham AL 35233-7333, USA; Emory University
School of Medicine, Atlanta, GA, USA.
Received June 27, 2012; accepted August 5, 2012; Epub August 20, 2012; Published September 15, 2012
Abstract: Mutation in the BRCA1 gene is associated with increased risk for hereditary breast and ovarian cancers. In sporadic
ovarian tumors, BRCA1 dysfunction is thought to be common. BRCA1 is a nuclear-cytoplasm shuttling protein. Our group has
previously reported that BRCA1 proteins, unlike K109R and cancer-predisposing mutant C61G BRCA1 proteins, bind the sole
SUMO E2-conjugating enzyme Ubc9. In this study, we examined the result of altered Ubc9 binding and knockdown on the
sub-cellular localization and growth inhibitory function of BRCA1 proteins in ovarian cancer cells. Using live imaging of YFP,
RFP-tagged BRCA1 and BRCA1a proteins, our results show enhanced cytoplasmic localization of K109R and C61G mutant
BRCA1 proteins in ES-2, NIHOVCAR3 and UWB 1.289 ovarian cancer cells. Down-regulation of Ubc9 in ovarian cancer cells
using Ubc9 siRNA resulted in cytoplasmic localization of BRCA1 and BRCA1a proteins. These mutant BRCA1a proteins were
impaired in their capacity to inhibit growth of ES-2 ovarian cancer cells. Several ovarian cancer cells, including a BRCA1-null
ovarian cancer cell line, showed higher levels of expression of Ubc9. This is the first study demonstrating the physiological link
between loss of Ubc9 binding and loss of growth suppression of disease-associated mutant BRCA1a proteins in ovarian
cancer cells. BRCA1, by turning off or on Ubc9 binding, regulates growth of ovarian cancers. (AJCR0000134).
Keywords: BRCA1, BRCA1a, Ubc9, Ovarian cancer, RING domain mutants, nuclear import, Growth suppression
Address all correspondence to:
Dr. Veena N Rao
Department of OB/GYN
Morehouse School of Medicine
Georgia Cancer Center for Excellence
Rm 10C011, Grady Health System
80 Jesse Hill Jr. Drive
Atlanta, Georgia 30303-3031, USA.
Tel: 404-489-9993; Fax: 404-489-9220
E-mail: vrao@msm.edu
Original Article
BRCA1 proteins regulate growth of ovarian cancer cells by tethering Ubc9
Yunlong Qin, Jingyao Xu, Kartik Aysola, Gabriela Oprea, Avinash Reddy, Roland Matthews, Joel Okoli, Alan Cantor, William E
Grizzle, Edward E Partridge, E Shyam P Reddy, Charles Landen, Veena N Rao
Cancer Biology Program, Department of OB/GYN; Department of Surgery Morehouse School of Medicine, Georgia Cancer Center
for Excellence, Grady Health System, Atlanta, GA 30303, USA; Department of Pathology, University of Alabama at Birmingham,
703 19th Street South, Birmingham, AL 35294-0007, USA; Department of Obstetrics & Gynecology, Division of Gynecological
Oncology, 618 20th Street South, University of Alabama at Birmingham, Birmingham AL 35233-7333, USA; Emory University
School of Medicine, Atlanta, GA, USA.
Received June 27, 2012; accepted August 5, 2012; Epub August 20, 2012; Published September 15, 2012
Abstract: Mutation in the BRCA1 gene is associated with increased risk for hereditary breast and ovarian cancers. In sporadic
ovarian tumors, BRCA1 dysfunction is thought to be common. BRCA1 is a nuclear-cytoplasm shuttling protein. Our group has
previously reported that BRCA1 proteins, unlike K109R and cancer-predisposing mutant C61G BRCA1 proteins, bind the sole
SUMO E2-conjugating enzyme Ubc9. In this study, we examined the result of altered Ubc9 binding and knockdown on the
sub-cellular localization and growth inhibitory function of BRCA1 proteins in ovarian cancer cells. Using live imaging of YFP,
RFP-tagged BRCA1 and BRCA1a proteins, our results show enhanced cytoplasmic localization of K109R and C61G mutant
BRCA1 proteins in ES-2, NIHOVCAR3 and UWB 1.289 ovarian cancer cells. Down-regulation of Ubc9 in ovarian cancer cells
using Ubc9 siRNA resulted in cytoplasmic localization of BRCA1 and BRCA1a proteins. These mutant BRCA1a proteins were
impaired in their capacity to inhibit growth of ES-2 ovarian cancer cells. Several ovarian cancer cells, including a BRCA1-null
ovarian cancer cell line, showed higher levels of expression of Ubc9. This is the first study demonstrating the physiological link
between loss of Ubc9 binding and loss of growth suppression of disease-associated mutant BRCA1a proteins in ovarian
cancer cells. BRCA1, by turning off or on Ubc9 binding, regulates growth of ovarian cancers. (AJCR0000134).
Keywords: BRCA1, BRCA1a, Ubc9, Ovarian cancer, RING domain mutants, nuclear import, Growth suppression
Address all correspondence to:
Dr. Veena N Rao
Department of OB/GYN
Morehouse School of Medicine
Georgia Cancer Center for Excellence
Rm 10C011, Grady Health System
80 Jesse Hill Jr. Drive
Atlanta, Georgia 30303-3031, USA.
Tel: 404-489-9993; Fax: 404-489-9220
E-mail: vrao@msm.edu
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American Journal of Cancer Research
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