Acetylation Directs Survivin Nuclear Localization to Repress STAT3 Oncogenic Activity

Abstract

The multiple functions of the oncofetal protein survivin are dependent on its selective expression patterns within immunochemically distinct subcellular pools. The mechanism by which survivin localizes to these compartments, however, is only partly understood. Here we show that nuclear accumulation of survivin is promoted by CREB-binding protein (CBP)-dependent acetylation on lysine 129 (129K, Lys-129). We demonstrate a mechanism by which survivin acetylation at this position results in its homodimerization, while deacetylation promotes the formation of survivin monomers that heterodimerize with CRM1 and facilitate its nuclear export. Using proteomic analysis, we identified the oncogenic transcription factor STAT3 as a binding partner of nuclear survivin. We show that acetylated survivin binds to the N-terminal transcriptional activation domain of the STAT3 dimer and represses STAT3 transactivation of target gene promoters. Using multiplex PCR and DNA sequencing, we identified a single-nucleotide polymorphism (A 3 G) at Lys-129 that exists as a homozygous mutation in a neuroblastoma cell line and corresponds with a defect in survivin nuclear localization. Our results demonstrate that the dynamic equilibrium between survivin acetylation and deacetylation at amino acid 129 determines its interaction with CRM1, its subsequent subcellular localization, and its ability to inhibit STAT3 transactivation, providing a potential route for therapeutic intervention in STAT3-dependent tumors.

Prognostic and biological significance of survivin expression in patients with diffuse large B-cell lymphoma treated with rituximab-CHOP therapy

“…25,63 However, survivin can also bind to STAT3 dimers and repress STAT3 transactivation of target gene promoters. 64 Thus, clarifying the mechanism underlying the association of STAT3-survivin coexpression with better overall survival and progression-free survival is difficult.…”

Nuclear Survivin: Cellular Consequences and Therapeutic Implications

“…Although survivin has a zinc finger in its BIR domain, this fold is distinct from zinc rich domains found in many TFs, and accordingly survivin itself cannot bind directly to DNA (Klein et al, 2006). However, it has been suggested that survivin suppresses the cytokine activated transcription factor, STAT3, and that this association may be regulated acetylation of survivin at lysine, K129, in the carboxyl alpha helix (Wang et al, 2010). Although the consequences of this interaction are not clear at present, it is nevertheless intriguing that this could be one reason to eliminate survivin from the nucleus.…”

“…Although the consequences of this interaction are not clear at present, it is nevertheless intriguing that this could be one reason to eliminate survivin from the nucleus. In this regard it is important to note that significant new insight in the mitosis field has revealed that survivin interacts directly with the NH 2 tail of histone H3, which protrudes from the nucleosome, and that this interaction is dependent upon phosphorylation of threonine 3 in histone H3's (Kelly et al, 2010;Wang et al, 2010). As this phosphorylation event is placed by the mitosis specific kinase, haspin, it is unclear whether such an interaction could occur in non-mitotic cells, however, indirect interactions in addition to direct binding between survivin and H2A also facilitates chromatin association (Kelly et al, 2010;Yamagishi et al, 2010), and borealin has been demonstrated to bind dsDNA directly in vitro (Klein et al, 2006).…”

“…Trafficking of survivin between the nucleus and cytoplasm is also susceptible to regulation by post-translational modifications, including acetylation and phosphorylation. Survivin acetylation, which occurs at K129, and is facilitated by the acetyl transferase CREB-binding protein (CBP), has been implicated in aiding survivin transit out of the nucleus (Wang et al, 2010), presumably by affecting the activity of the C-terminal NES (Engelsma et al, 2007). Glucogen synthase kinase 3β (GSK3β) facilitates translocation of survivin into the nucleus, but whether phosphorylation of survivin by GSK3β is involved is not yet known (Li et al, 2008).…”

Association between survivin −31G>C promoter polymorphism and cancer risk: a meta-analysis

“…Twelve of these articles did not explore the survivin À31G/C polymorphism and were excluded. [28][29][30][31][32][33][34][35][36][37][38][39] Four of these articles did not explore cancer risk and were excluded. [40][41][42][43] Finally, 13 case-control studies and 1 cohort study 44 that comprised a total of 3485 cancer cases and 3964 controls were included in our meta-analysis, and are presented in Table 1.…”