Interplay among BRCA1, SIRT1, and Survivin during BRCA1-Associated Tumorigenesis

Abstract

Summary Germline mutations of BRCA1 predispose women to breast and ovarian cancers. However, the downstream mediators of BRCA1 function in tumor suppression remain elusive. We found that human BRCA1-associated breast cancers have lower levels of SIRT1 than their normal controls. We further demonstrated that mammary tumors from BRCA1 mutant mice have low levels of SIRT1 and high levels of Survivin, which is reversed by induced expression of BRCA1. BRCA1 binds to the SIRT1 promoter and increases SIRT1 expression, which in turn inhibits Survivin by changing the epigenetic modification of histone H3. Absence of SIRT1 blocks the regulation of Survivin by BRCA1. Furthermore, we demonstrated that activation of SIRT1 and inhibition of Survivin expression by resveratrol elicit a more profound inhibitory effect on BRCA1-mutant cancer cells than on BRCA1-wild type cancer cells both in vitro and in vivo. These findings suggest that resveratrol treatment serves as an excellent strategy for targeted therapy for BRCA1-associated breast cancer.

Association of SIRT1 and HMGA1 expression in non-small cell lung cancer

“…Previous studies revealed that SIRT1 can act as a tumor suppressor by repressing a number of oncogenes (39)(40)(41). By contrast, SIRT1 expression has been observed to be increased in various human Table I.…”

BRCA1 affects global DNA methylation through regulation of DNMT1

“…BRCA1 is a well-established transcription factor because it regulates expression of many genes, some of which include p21 [44], Gadd45 [40,45], Mad2 [42], Sirt1 [46], and Igf axis members [39]. The C-terminal region of BRCA1 contains two BRCT domains that interact with multiple transcription activators and corepressors.…”

SirT1-null mice develop tumors at normal rates but are poorly protected by resveratrol

“…Several reports show data consistent with SirT1 having an inhibitory effect (Langley et al, 2002;Ota et al, 2006;Abdelmohsen et al, 2007;van der Veer et al, 2007;Huang et al, 2008), a promoting effect (Chua et al, 2005) or no effect (Michishita et al, 2005;Kamel, Boily and McBurney, unpublished data) on cellular senescence. SirT1 expression can be repressed by HIC1 (Chen et al, 2005b), activated by BRCA1 (Wang et al, 2008b), and both suppressed (in fed cells) and activated (with FoxO3a in starved cells) by p53 (Nemoto et al, 2004), three tumorsuppressor proteins. Moreover, some targets of SirT1 deacetylation, including p53 (Luo et al, 2001;Vaziri et al, 2001), p73 (Dai et al, 2007), nuclear factor-kB (NF-kB) (Yeung et al, 2004;Chen et al, 2005a) and AR (Fu et al, 2006), are important proteins involved in cancer.…”