SIK1 Couples LKB1 to p53-Dependent Anoikis and Suppresses Metastasis

Sci. Signal., 21 July 2009
Vol. 2, Issue 80, p. ra35
DOI: 10.1126/scisignal.2000369

SIK1 Couples LKB1 to p53-Dependent Anoikis and Suppresses Metastasis

  1. Hailing Cheng1,2,
  2. Pixu Liu1,2,*,
  3. Zhigang C. Wang1,3,*,
  4. Lihua Zou1,3,*,
  5. Stephanie Santiago1,2,
  6. Victoria Garbitt1,2,
  7. Ole V. Gjoerup4,
  8. J. Dirk Iglehart1,3,
  9. Alexander Miron1,3,
  10. Andrea L. Richardson1,3,
  11. William C. Hahn5,6,7,, and
  12. Jean J. Zhao1,2,3,
  1. 1Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
  2. 2Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
  3. 3Department of Surgery, Brigham and Women’s Hospital, Boston, MA 02115, USA.
  4. 4Molecular Virology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
  5. 5Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
  6. 6Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
  7. 7Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
  1. To whom correspondence should be addressed. E-mail:jean_zhao{at}dfci.harvard.edu (J.J.Z) and william_hahn{at}dfci.harvard.edu (W.C.H.)
  • * These authors contributed equally to this work.

Abstract

Resistance to anoikis, the subtype of apoptosis triggered by lack of adhesion, contributes to malignant transformation and the development of metastasis. Although several lines of evidence suggest that p53 plays a critical role in anoikis, the pathway(s) that connect cell detachment to p53 remain undefined. Here, through the use of a kinome-wide loss-of-function screen, we identify the serine-threonine kinase SIK1 (salt-inducible kinase 1) as a regulator of p53-dependent anoikis. Inactivation of SIK1 compromised p53 function in anoikis and allowed cells to grow in an anchorage-independent manner. In vivo, SIK1 loss facilitated metastatic spread and survival of disseminated cells as micrometastases in lungs. The presence of functional SIK1 was required for the activity of the kinase LKB1 in promoting p53-dependent anoikis and suppressing anchorage-independent growth, Matrigel invasion, and metastatic potential. In human cancers, decreased expression of the gene encoding SIK1 closely correlated with development of distal metastases in breast cancers from three independent cohorts. Together, these findings indicate that SIK1 links LKB1 to p53-dependent anoikis and suppresses metastasis.

Citation:

H. Cheng, P. Liu, Z. C. Wang, L. Zou, S. Santiago, V. Garbitt, O. V. Gjoerup, J. D. Iglehart, A. Miron, A. L. Richardson, W. C. Hahn, and J. J. Zhao, SIK1 Couples LKB1 to p53-Dependent Anoikis and Suppresses Metastasis. Sci. Signal. 2, ra35 (2009).

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K. T. Chan, S. B. Asokan, S. J. King, T. Bo, E. S. Dubose, W. Liu, M. E. Berginski, J. M. Simon, I. J. Davis, S. M. Gomez et al.
JCB 207, 299-315 (27 October 2014)

Contribution of p53 to Metastasis
E. Powell, D. Piwnica-Worms, and H. Piwnica-Worms
Cancer Discovery 4, 405-414 (1 April 2014)

AMPK: A Contextual Oncogene or Tumor Suppressor?
J. Liang, and G. B. Mills
Cancer Res. 73, 2929-2935 (15 May 2013)

Supervillin-mediated Suppression of p53 Protein Enhances Cell Survival
Z. Fang, and E. J. Luna
J Biol Chem 288, 7918-7929 (15 March 2013)

Mechanisms that link the oncogenic epithelial-mesenchymal transition to suppression of anoikis
S. M. Frisch, M. Schaller, and B. Cieply
J. Cell Sci. 126, 21-29 (1 January 2013)

Lkb1 regulates organogenesis and early oncogenesis along AMPK-dependent and -independent pathways
B. Lo, G. Strasser, M. Sagolla, C. D. Austin, M. Junttila, and I. Mellman
JCB 199, 1117-1130 (24 December 2012)

Salt-inducible kinase 1 regulates E-cadherin expression and intercellular junction stability
K. Eneling, L. Brion, V. Pinto, M. J. Pinho, J. I. Sznajder, N. Mochizuki, K. Emoto, P. Soares-da-Silva, and A. M. Bertorello
FASEB J. 26, 3230-3239 (1 August 2012)

A Pathway for the Control of Anoikis Sensitivity by E-Cadherin and Epithelial-to-Mesenchymal Transition
S. Kumar, S. H. Park, B. Cieply, J. Schupp, E. Killiam, F. Zhang, D. L. Rimm, and S. M. Frisch
Mol. Cell. Biol. 31, 4036-4051 (1 October 2011)

Making sense of cancer genomic data
L. Chin, W. C. Hahn, G. Getz, and M. Meyerson
Genes Dev. 25, 534-555 (15 March 2011)

Alternative cell death mechanisms in development and beyond
J. Yuan, and G. Kroemer
Genes Dev. 24, 2592-2602 (1 December 2010)

Understanding Micrometastatic Disease and Anoikis Resistance in Ewing Family of Tumors and Osteosarcoma
S. J. Strauss, T. Ng, A. Mendoza-Naranjo, J. Whelan, and P. H. B. Sorensen
The Oncologist 15, 627-635 (1 June 2010)

Tumor Suppression by LKB1: SIK-ness Prevents Metastasis
R. J. Shaw, T. Ng, A. Mendoza-Naranjo, J. Whelan, and P. H. B. Sorensen
Sci Signal 2, pe55-pe55 (1 September 2009)

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