BRCA1-associated epigenetic regulation of p73 mediates an effector pathway for chemosensitivity in ovarian carcinoma.
The majority of tumors arising in BRCA1 mutation carriers exhibit inactivation of p53, a key effector of cell death after DNA damage. Despite the loss of p53, BRCA1-deficient tumor cells exhibit increased sensitivity to cisplatin, and patients with BRCA1-associated ovarian carcinomas experience improved outcomes with platinum-based chemotherapy compared with sporadic cases. Although it is known that chemosensitivity in BRCA1-associated cancers is associated with unrepaired DNA damage, the specific effector pathway mediating the cellular response to platinum-induced damage in these tumors is poorly understood. Here, we show that the p53-related gene p73, encoding a proapoptotic protein that is linked to chemosensitivity in many settings, is upregulated through a novel epigenetic mechanism in both human and murine models of BRCA1-associated ovarian carcinoma. BRCA1-deficient ovarian carcinoma cells exhibit hypermethylation within a p73 regulatory region, which includes the binding site for the p73 transcriptional repressor ZEB1, leading to the abrogation of ZEB1 binding and increased expression of transactivating p73 isoforms (TAp73). Cisplatin chemotherapy induces TAp73 target genes specifically in BRCA1-deficient cells, and knockdown of TAp73 in these cells causes chemoresistance while having little or no effect on BRCA1-expressing tumor cells. In primary ovarian carcinomas, ZEB1 binding site methylation and TAp73 expression correlate with BRCA1 status and with clinical response. Together, these findings uncover a novel regulatory mechanism that supports the contribution of TAp73 as an important mediator of the response to platinum chemotherapy in a subset of ovarian carcinomas. TAp73 might represent a response predictor and potential therapeutic target for enhancing chemosensitivity in this disease.
Ibrahim
Nageatte
N
Massachusetts General Hospital Cancer Center and Harvard Medical School, Vincent Center for Reproductive Biology, Massachusetts General Hospital, Boston, Massachusetts, USA.
He
Lei
L
Leong
Chee-Onn
CO
Xing
Deyin
D
Karlan
Beth Y
BY
Swisher
Elizabeth M
EM
Rueda
Bo R
BR
Orsulic
Sandra
S
Ellisen
Leif W
LW
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019313:BRCA1 Protein / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics*; D001665:Binding Sites; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D020033:Protein Isoforms; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics*; D000071799:Zinc Finger E-box-Binding Homeobox 1
D000970:Antineoplastic Agents; D019313:BRCA1 Protein; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D020033:Protein Isoforms; C000606460:TP73 protein, human; D014157:Transcription Factors; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; C486307:ZEB1 protein, human; C519422:ZEB1 protein, mouse; D000071799:Zinc Finger E-box-Binding Homeobox 1; C454920:delta Np73, mouse; D002945:Cisplatin
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