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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Bhardwaj, Abhishek Das, Sanjeev |
| Description | Author Affiliation: Bhardwaj A ( Molecular Oncology Laboratory, National Institute of Immunology, New Delhi-110067, India.); Das S ( Molecular Oncology Laboratory, National Institute of Immunology, New Delhi-110067, India sdas@nii.ac.in.); |
| 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. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 5 |
| Volume Number | 113 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2016-02-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Carrier Proteins Metabolism Cell Nucleus Membrane Proteins Oncogenes Sirtuins Thyroid Hormones Acetylation Animals Hep G2 Cells Mice Protein Transport Physiology Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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