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Deacetylation Assays to Unravel the Interplay between Sirtuins SIRT2 and Specific Protein-substrates
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Deacetylation Assays to Unravel the Interplay between Sirtuins SIRT2 and Specific Protein-substrates

Published on: February 27, 2016

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SIRT6 deacetylates PKM2 to suppress its nuclear localization and oncogenic functions

Abhishek Bhardwaj1, Sanjeev Das2

  • 1Molecular Oncology Laboratory, National Institute of Immunology, New Delhi-110067, India.

Proceedings of the National Academy of Sciences of the United States of America
|January 21, 2016
PubMed

Insights

SIRT6 (sirtuin 6) deacetylates nuclear PKM2 (pyruvate kinase M2), inhibiting its oncogenic functions and suppressing tumor growth. This deacetylation leads to PKM2 nuclear export, reducing cancer cell proliferation and metastasis.

Area of Science:

  • Molecular Biology
  • Oncology
  • Biochemistry

Background:

  • SIRT6 (sirtuin 6) is a deacetylase involved in genome stability, metabolism, and tumorigenesis.
  • The precise role of SIRT6's deacetylase activity in its tumor-suppressor functions remains unclear.

Purpose of the Study:

  • To investigate the role of SIRT6 deacetylase activity in regulating nuclear PKM2 (pyruvate kinase M2).
  • To elucidate the mechanism by which SIRT6 suppresses PKM2's oncogenic functions.

Main Methods:

  • Investigated SIRT6 binding and deacetylation of nuclear PKM2 at lysine 433.
  • Identified exportin 4 as the transporter for PKM2 nuclear export.
  • Utilized mouse tumor models to assess SIRT6's role in tumor suppression and metastasis.

Main Results:

  • SIRT6 deacetylates nuclear PKM2, causing its export from the nucleus via exportin 4.
  • This deacetylation abolishes PKM2's nuclear protein kinase and transcriptional coactivator functions.
  • SIRT6-mediated PKM2 deacetylation suppressed tumor cell proliferation, migration, invasiveness, and metastasis in mouse models.
  • Reduced SIRT6 levels correlated with increased nuclear acetylated PKM2 in hepatocellular carcinoma.

Conclusions:

  • SIRT6 suppresses PKM2 oncogenic functions through deacetylation and nuclear export.
  • Deacetylation of PKM2 is crucial for SIRT6's tumor-suppressive activity.
  • These findings highlight the importance of SIRT6 deacetylase activity in cancer suppression.
Keywords:
PKM2SIRT6deacetylationtumor suppressor

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