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Functional dissection of lysine deacetylases reveals that HDAC1 and p300 regulate AMPK

Nature volume 482, pages 251–255 (2012)Cite this article

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A Retraction to this article was published on 06 November 2013

Abstract

First identified as histone-modifying proteins, lysine acetyltransferases (KATs) and deacetylases (KDACs) antagonize each other through modification of the side chains of lysine residues in histone proteins1. Acetylation of many non-histone proteins involved in chromatin, metabolism or cytoskeleton regulation were further identified in eukaryotic organisms2,3,4,5,6, but the corresponding enzymes and substrate-specific functions of the modifications are unclear. Moreover, mechanisms underlying functional specificity of individual KDACs7 remain enigmatic, and the substrate spectra of each KDAC lack comprehensive definition. Here we dissect the functional specificity of 12 critical human KDACs using a genome-wide synthetic lethality screen8,9,10,11,12,13 in cultured human cells. The genetic interaction profiles revealed enzyme–substrate relationships between individual KDACs and many important substrates governing a wide array of biological processes including metabolism, development and cell cycle progression. We further confirmed that acetylation and deacetylation of the catalytic subunit of the adenosine monophosphate-activated protein kinase (AMPK), a critical cellular energy-sensing protein kinase complex, is controlled by the opposing catalytic activities of HDAC1 and p300. Deacetylation of AMPK enhances physical interaction with the upstream kinase LKB1, leading to AMPK phosphorylation and activation, and resulting in lipid breakdown in human liver cells. These findings provide new insights into previously underappreciated metabolic regulatory roles of HDAC1 in coordinating nutrient availability and cellular responses upstream of AMPK, and demonstrate the importance of high-throughput genetic interaction profiling to elucidate functional specificity and critical substrates of individual human KDACs potentially valuable for therapeutic applications.

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Figure 1: Overview of human KDAC genetic interaction screen.
Figure 2: Negative genetic interactions and enzyme–substrate relationship between HDAC1 and PRKAA1.
Figure 3: Deacetylation of PRKAA1 increases its phosphorylation and activity.
Figure 4: Deacetylation of PRKAA1 specifically enhances its physical interaction with LKB1 kinase.

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Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

Microarray data were deposited in the Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo) under accession number GSE29662.

References

  1. Yang, X. J. & Seto, E. The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men. Nature Rev. Mol. Cell Biol. 9, 206–218 (2008)

    Article  CAS  Google Scholar 

  2. Lin, Y. Y. et al. Protein acetylation microarray reveals that NuA4 controls key metabolic target regulating gluconeogenesis. Cell 136, 1073–1084 (2009)

    Article  CAS  Google Scholar 

  3. Choudhary, C. et al. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 325, 834–840 (2009)

    Article  ADS  CAS  Google Scholar 

  4. Kim, S. C. et al. Substrate and functional diversity of lysine acetylation revealed by a proteomics survey. Mol. Cell 23, 607–618 (2006)

    Article  CAS  Google Scholar 

  5. Zhao, S. et al. Regulation of cellular metabolism by protein lysine acetylation. Science 327, 1000–1004 (2010)

    Article  ADS  CAS  Google Scholar 

  6. Wellen, K. E. et al. ATP-citrate lyase links cellular metabolism to histone acetylation. Science 324, 1076–1080 (2009)

    Article  ADS  CAS  Google Scholar 

  7. Haberland, M., Montgomery, R. L. & Olson, E. N. The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nature Rev. Genet. 10, 32–42 (2009)

    Article  CAS  Google Scholar 

  8. Scholl, C. et al. Synthetic lethal interaction between oncogenic KRAS dependency and STK33 suppression in human cancer cells. Cell 137, 821–834 (2009)

    Article  CAS  Google Scholar 

  9. Luo, J. et al. A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene. Cell 137, 835–848 (2009)

    Article  CAS  Google Scholar 

  10. Silva, J. M. et al. Profiling essential genes in human mammary cells by multiplex RNAi screening. Science 319, 617–620 (2008)

    Article  CAS  Google Scholar 

  11. Schlabach, M. R. et al. Cancer proliferation gene discovery through functional genomics. Science 319, 620–624 (2008)

    Article  CAS  Google Scholar 

  12. Luo, B. et al. Highly parallel identification of essential genes in cancer cells. Proc. Natl Acad. Sci. USA 105, 20380–20385 (2008)

    Article  ADS  CAS  Google Scholar 

  13. Barbie, D. A. et al. Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature 462, 108–112 (2009)

    Article  ADS  CAS  Google Scholar 

  14. Stark, C. et al. The BioGRID Interaction Database: 2011 update. Nucleic Acids Res. 39, D698–D704 (2011)

    Article  ADS  CAS  Google Scholar 

  15. Haberland, M., Johnson, A., Mokalled, M. H., Montgomery, R. L. & Olson, E. N. Genetic dissection of histone deacetylase requirement in tumor cells. Proc. Natl Acad. Sci. USA 106, 7751–7755 (2009)

    Article  ADS  CAS  Google Scholar 

  16. Lin, Y. Y. et al. A comprehensive synthetic genetic interaction network governing yeast histone acetylation and deacetylation. Genes Dev. 22, 2062–2074 (2008)

    Article  CAS  Google Scholar 

  17. Costanzo, M. et al. The genetic landscape of a cell. Science 327, 425–431 (2010)

    Article  ADS  CAS  Google Scholar 

  18. Hassig, C. A. et al. A role for histone deacetylase activity in HDAC1-mediated transcriptional repression. Proc. Natl Acad. Sci. USA 95, 3519–3524 (1998)

    Article  ADS  CAS  Google Scholar 

  19. Grozinger, C. M. & Schreiber, S. L. Deacetylase enzymes: biological functions and the use of small-molecule inhibitors. Chem. Biol. 9, 3–16 (2002)

    Article  CAS  Google Scholar 

  20. Hardie, D. G. AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nature Rev. Mol. Cell Biol. 8, 774–785 (2007)

    Article  CAS  Google Scholar 

  21. Xiao, B. et al. Structure of mammalian AMPK and its regulation by ADP. Nature 472, 230–233 (2011)

    Article  ADS  CAS  Google Scholar 

  22. Oakhill, J. S. et al. AMPK is a direct adenylate charge-regulated protein kinase. Science 332, 1433–1435 (2011)

    Article  ADS  CAS  Google Scholar 

  23. Hawley, S. A. et al. Characterization of the AMP-activated protein kinase kinase from rat liver and identification of threonine 172 as the major site at which it phosphorylates AMP-activated protein kinase. J. Biol. Chem. 271, 27879–27887 (1996)

    Article  CAS  Google Scholar 

  24. Hawley, S. A. et al. Complexes between the LKB1 tumor suppressor, STRADα/β and MO25α/β are upstream kinases in the AMP-activated protein kinase cascade. J. Biol. 2, 28 (2003)

    Article  Google Scholar 

  25. Suter, M. et al. Dissecting the role of 5′-AMP for allosteric stimulation, activation, and deactivation of AMP-activated protein kinase. J. Biol. Chem. 281, 32207–32216 (2006)

    Article  CAS  Google Scholar 

  26. Bungard, D. et al. Signaling kinase AMPK activates stress-promoted transcription via histone H2B phosphorylation. Science 329, 1201–1205 (2010)

    Article  ADS  CAS  Google Scholar 

  27. Bolden, J. E., Peart, M. J. & Johnstone, R. W. Anticancer activities of histone deacetylase inhibitors. Nature Rev. Drug Discov. 5, 769–784 (2006)

    Article  CAS  Google Scholar 

  28. Kazantsev, A. G. & Thompson, L. M. Therapeutic application of histone deacetylase inhibitors for central nervous system disorders. Nature Rev. Drug Discov. 7, 854–868 (2008)

    Article  CAS  Google Scholar 

  29. Huangfu, D. et al. Induction of pluripotent stem cells by defined factors is greatly improved by small-molecule compounds. Nature Biotechnol. 26, 795–797 (2008)

    Article  CAS  Google Scholar 

  30. Bantscheff, M. et al. Chemoproteomics profiling of HDAC inhibitors reveals selective targeting of HDAC complexes. Nature Biotechnol. 29, 255–265 (2011)

    Article  CAS  Google Scholar 

  31. Eisen, M. B., Spellman, P. T., Brown, P. O. & Botstein, D. Cluster analysis and display of genome-wide expression patterns. Proc. Natl Acad. Sci. USA 95, 14863–14868 (1998)

    Article  ADS  CAS  Google Scholar 

  32. Thomas, P. D. et al. PANTHER: a library of protein families and subfamilies indexed by function. Genome Res. 13, 2129–2141 (2003)

    Article  CAS  Google Scholar 

  33. Mi, H. et al. PANTHER version 7: improved phylogenetic trees, orthologs and collaboration with the Gene Ontology Consortium. Nucleic Acids Res. 38, D204–D210 (2010)

    Article  CAS  Google Scholar 

  34. Berriz, G. F., Beaver, J. E., Cenik, C., Tasan, M. & Roth, F. P. Next generation software for functional trend analysis. Bioinformatics 25, 3043–3044 (2009)

    Article  CAS  Google Scholar 

  35. Jayapandian, M. et al. Michigan Molecular Interactions (MiMI): putting the jigsaw puzzle together. Nucleic Acids Res. 35, D566–D571 (2007)

    Article  CAS  Google Scholar 

  36. Nakatani, Y. & Ogryzko, V. Immunoaffinity purification of mammalian protein complexes. Methods Enzymol. 370, 430–444 (2003)

    Article  CAS  Google Scholar 

  37. Hwang, J. T. et al. Genistein, EGCG, and capsaicin inhibit adipocyte differentiation process via activating AMP-activated protein kinase. Biochem. Biophys. Res. Commun. 338, 694–699 (2005)

    Article  CAS  Google Scholar 

  38. Saldanha, A. J. Java Treeview—extensible visualization of microarray data. Bioinformatics 20, 3246–3248 (2004)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank H. Zhu, S.-L. Yu and L.-P. Chow for gifts of reagents, J. Lu for IMR-90 cells, Department of Medical Science, National Taiwan University for technical help with sequencing, and the National RNAi Core Facility, Academia Sinica for reagents and technical support with RNAi screen. We are grateful to P. Meluh and members of the Lin and Boeke laboratories for discussions. We thank D. Root for discussions. This study was supported by National Science Council grants NSC 98-2320-B-002-057-, NSC 99-2320-B-002-057- and NSC 100-2325-002-044- (Y.-y.L.), National Taiwan University Frontier and Innovative Research 99R71424 (Y.-y.L.), National Taiwan University College of Medicine and National Taiwan University Hospital Excellent Translational Medicine Research Project 99C101-603 (Y.-y.L. and J.-y.L.), National Health Research Institutes Career Development grant NHRI-EX100-10017BC (Y.-y.L.), Liver Disease Prevention and Treatment Research Foundation (Y.-y.L. and J.-y.L.) and NIH Common Fund grant U54 RR 020839 (J.D.B.).

Author information

Author notes

  1. Samara Kiihl and Yasir Suhail: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei 100, Taiwan,

    Yu-yi Lin, Shang-Yun Liu & Yi-hsuan Chou

  2. Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan,

    Yu-yi Lin & Jin-ying Lu

  3. Department of Oncology, National Taiwan University Hospital, Taipei 100, Taiwan,

    Yu-yi Lin

  4. Department of Biostatistics, Johns Hopkins Bloomberg, School of Public Health, Baltimore, 21231, Maryland, USA

    Samara Kiihl & Rafael Irizarry

  5. Department of Biomedical Engineering, Johns Hopkins University, Baltimore, 21218, Maryland, USA

    Yasir Suhail & Joel S. Bader

  6. Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Zheng Kuang & Jef D. Boeke

  7. The High Throughput Biology Center, The Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Zheng Kuang & Jef D. Boeke

  8. Department of Laboratory Medicine, National Taiwan University Hospital, Taipei 100, Taiwan,

    Jin-ying Lu

  9. National RNAi Core Facility, Institute of Molecular Biology, Academia Sinica, Taipei 115, Taiwan,

    Chin Ni Khor & Chi-Long Lin

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Contributions

Y.-y.L. and J.D.B. designed the experiments, with help from J.-y.L. Y.-y.L. and Y.-h.C. performed the primary screens, with help from C.N.K. and C.-L.L. Validation and further functional categorization experiments were performed by Y.-y.L., S.-Y.L. and Z.K. S.K. and Y.S. performed computational analyses, supervised by R.I. and J.S.B., respectively. Y.-y.L., J.-y.L. and J.D.B. wrote the manuscript. All authors discussed results and edited the manuscript.

Corresponding authors

Correspondence to Yu-yi Lin or Jef D. Boeke.

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The authors declare no competing financial interests.

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This file contains Supplementary Figures 1-18 with legends and Supplementary Tables 1-8. (PDF 13084 kb)

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Lin, Yy., Kiihl, S., Suhail, Y. et al. Functional dissection of lysine deacetylases reveals that HDAC1 and p300 regulate AMPK. Nature 482, 251–255 (2012). https://doi.org/10.1038/nature10804

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