title: BRCA1 as a nicotinamide adenine dinucleotide (NAD)-dependent metabolic switch in ovarian cancer.
abstract: Both hereditary factors (e.g., BRCA1) and nicotinamide adenine dinucleotide (NAD)-dependent metabolic pathways are implicated in the initiation and progression of ovarian cancer. However, whether crosstalk exists between BRCA1 and NAD metabolism remains largely unknown. Here, we showed that: (i) BRCA1 inactivation events (mutation and promoter methylation) were accompanied by elevated levels of NAD; (ii) the knockdown or overexpression of BRCA1 was an effective way to induce an increase or decrease of nicotinamide phosphoribosyltransferase (Nampt)-related NAD synthesis, respectively; and (iii) BRCA1 expression patterns were inversely correlated with NAD levels in human ovarian cancer specimens. In addition, it is worth noting that: (i) NAD incubation induced increased levels of BRCA1 in a concentration-dependent manner; (ii) Nampt knockdown-mediated reduction in NAD levels was effective at inhibiting BRCA1 expression; and (iii) the overexpression of Nampt led to higher NAD levels and a subsequent increase in BRCA1 levels in primary ovarian cancer cells and A2780, HO-8910 and ES2 ovarian cancer cell lines. These results highlight a novel link between BRCA1 and NAD. Our findings imply that genetic (e.g., BRCA1 inactivation) and NAD-dependent metabolic pathways are jointly involved in the malignant progression of ovarian cancer.
authors.affiliation: a Department of Obstetrics and Gynecology ; Shengjing Hospital of China Medical University ; Shenyang , China.
authors.forename: Da
authors.initials: D
authors.lastname: Li
authors.forename: Na-Na
authors.initials: NN
authors.lastname: Chen
authors.forename: Ji-Min
authors.initials: JM
authors.lastname: Cao
authors.forename: Wu-Ping
authors.initials: WP
authors.lastname: Sun
authors.forename: Yi-Ming
authors.initials: YM
authors.lastname: Zhou
authors.forename: Chun-Yan
authors.initials: CY
authors.lastname: Li
authors.forename: Xiu-Xia
authors.initials: XX
authors.lastname: Wang
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D024682:BRCA2 Protein / Q000378:metabolism; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D008745:Methylation; D009154:Mutation; D009243:NAD / Q000378:metabolism*; D054409:Nicotinamide Phosphoribosyltransferase / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000378:metabolism*; D011401:Promoter Regions, Genetic
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D016207:Cytokines; D009243:NAD; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human
keywords: BRCA1; BRCA1, breast cancer type 1 susceptibility protein; CtBP, C-terminal binding proteins; NAD; NAD, nicotinamide adenine dinucleotide; Nampt, nicotinamide phosphoribosyltransferase; NADH; Nampt; PCR, polymerase chain reaction; ovarian cancer; shRNAs, short hairpin ribonucleic acids