title: Effect of the BRCA1-SIRT1-EGFR axis on cisplatin sensitivity in ovarian cancer.
abstract: There is accumulating evidence that breast cancer 1 (BRCA1), sirtuin 1 (SIRT1), and epidermal growth factor receptor (EGFR) help to modulate cisplatin cytotoxicity. The role of dynamic crosstalk among BRCA1, SIRT1, and EGFR in cisplatin sensitivity remains largely unknown. We found that BRCA1, SIRT1, and EGFR levels were increased in cisplatin-resistant ovarian cancers compared with those in cisplatin-sensitive ovarian cancers. Hypomethylation in the BRCA1 promoter was associated with BRCA1 activation, significantly elevated SIRT1 levels, decreased nicotinamide adenine dinucleotide (NAD)-mediated SIRT1 activity, and decreased EGFR levels. Treatment with 5 and 10 μg/ml cisplatin induced a gradual increase in BRCA1 and SIRT1 levels and a gradual decrease in NAD levels and NAD-mediated SIRT1 activity, whereas EGFR levels were increased or decreased by treatment with 5 or 10 μg/ml cisplatin, respectively. The overexpression of SIRT1 or the enhancement of SIRT1 activity synergistically enhanced the BRCA1-mediated effects on EGFR transcription. In contrast, the knockdown of SIRT1 or the inhibition of SIRT1 activity inhibited the BRCA1-mediated effects on EGFR transcription. BRCA1 regulates EGFR through a BRCA1-mediated balance between SIRT1 expression and activity. Those results improve our understanding of the basic molecular mechanism underlying BRCA1-related cisplatin resistance in ovarian cancer.
authors.affiliation: Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University Shenyang 110004, China.
authors.forename: Da
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Clinical Epidemiology, Shengjing Hospital of China Medical University Shenyang 110004, China.
authors.forename: Qi-Jun
authors.initials: QJ
authors.lastname: Wu
authors.affiliation: Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University Shenyang 110004, China.
authors.forename: Fang-Fang
authors.initials: FF
authors.lastname: Bi
authors.affiliation: Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University Shenyang 110004, China.
authors.forename: Si-Lei
authors.initials: SL
authors.lastname: Chen
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Harvard Institutes of Medicine, Harvard Medical School Boston, MA 02115, USA.
authors.forename: Yi-Ming
authors.initials: YM
authors.lastname: Zhou
authors.affiliation: Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University Shenyang 110001, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University Shenyang 110004, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yang
keywords: BRCA1; EGFR; SIRT1; cisplatin; ovarian cancer