SIRT6 deacetylates PKM2 to suppress its nuclear localization and oncogenic functions

Abstract

SIRT6 (sirtuin 6) is a member of sirtuin family of deacetylases involved in diverse processes including genome stability, metabolic homeostasis, and tumorigenesis. However, the role of SIRT6 deacetylase activity in its tumor-suppressor functions is not well understood. Here we report that SIRT6 binds to and deacetylates nuclear PKM2 (pyruvate kinase M2) at the lysine 433 residue. PKM2 is a glycolytic enzyme with nonmetabolic nuclear oncogenic functions. SIRT6-mediated deacetylation results in PKM2 nuclear export. We further have identified exportin 4 as the specific transporter mediating PKM2 nuclear export. As a result of SIRT6-mediated deacetylation, PKM2 nuclear protein kinase and transcriptional coactivator functions are abolished. Thus, SIRT6 suppresses PKM2 oncogenic functions, resulting in reduced cell proliferation, migration potential, and invasiveness. Furthermore, studies in mouse tumor models demonstrate that PKM2 deacetylation is integral to SIRT6-mediated tumor suppression and inhibition of metastasis. Additionally, reduced SIRT6 levels correlate with elevated nuclear acetylated PKM2 levels in increasing grades of hepatocellular carcinoma. These findings provide key insights into the pivotal role of deacetylase activity in SIRT6 tumor-suppressor functions.) is a member of the highly conserved sirtuin family of NAD + -dependent enzymes and plays a key role in DNA repair, telomere maintenance, and cellular metabolic processes. It exhibits diverse enzymatic activities including NAD + -dependent deacetylation and mono-ADP ribosylation. SIRT6 deacetylates telomeric histone H3 at lysine 9 (H3K9) and lysine 56 residues (H3K56) (1, 2). SIRT6-mediated deacetylation of telomeric H3K9 is required for the stable association of the Werner syndrome protein with telomeric chromatin for proper telomere function. SIRT6 also interacts with the NF-κB RELA subunit, deacetylates H3K9 at NF-κB target gene promoters, and attenuates NF-κB-mediated apoptosis and senescence (3). Likewise, SIRT6 also binds to hypoxia-inducible factor 1-alpha (HIF1α), deacetylates H3K9 at HIF1α target gene promoters, and regulates glucose homeostasis (4). SIRT6 also interacts with and deacetylates CtIP [C-terminal binding protein (CtBP) interacting protein] to promote the repair of DNA double-strand breaks by homologous recombination (5). SIRT6 mono-ADP ribosylates PARP1 to stimulate the repair of DNA double-strand breaks in response to oxidative stress (6).Several recent studies report that SIRT6 functions as a tumor suppressor. It was observed that loss of SIRT6 promotes tumor formation even without the activation of known oncogenes (7). Furthermore, SIRT6 was found to be down-regulated in pancreatic and colorectal cancers. Down-regulation of SIRT6 also has been reported in hepatocellular carcinoma (8, 9). Elevated c-JUN levels in hepatocellular carcinoma down-regulate SIRT6 expression in a c-FOS-dependent manner (8). Recently, naturally occurring cancer-associated point mutations were identified in SIRT6 that result in its loss of tumor-su...

Targeting immunometabolism as an anti-inflammatory strategy

“…Events like acetylation of PKM2 by p300 acetyltransferase, sumoylation by SUMO-E3 ligase, and binding of PKM2 to Jumonji C domain-containing dioxygenase 5 (JMJD5) promote nuclear translocation, whereas deacetylation of PKM2 at lysine 433 by Sirt 6 and tetramerization by the glycolytic intermediate fructose 1,6-bis-phosphate and small molecules such as TEPP-46 and DASA-58 all prevent nuclear translocation. 136,[145][146][147][148][149] PKM2 has been shown to play a central role in cancer biology; facilitating cancer cell proliferation, lactate production, as well as DNA and lipid synthesis. 150 Importantly, PKM2 also regulates immune responses, driving aerobic glycolysis and the expression of pro-inflammatory cytokines in LPS-activated macrophages.…”

SIRT6: Novel Mechanisms and Links to Aging and Disease

“…In the nucleus, PKM2 has additional oncogenic effects as a kinase and transcriptional co-activator of β-catenin, but deacetylation by SIRT6 results in nuclear export of PKM2 and loss of these tumorigenic functions [58] (Figure 3f). Anti-proliferative and pro-apoptotic effects of SIRT6 have also been observed in lung, ovarian, glioma, and other cancer cell types, and likely contribute to its tumor suppressive activity [11, 59].…”

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“…). Nuclear activities of PKM2, specifically in regulating cytokine production, are considered a “moonlighting function,” implicating basic metabolic regulators in directly affecting cellular behavior …”