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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

Hailing Cheng1,2, Pixu Liu1,2*, Zhigang C. Wang1,3*, Lihua Zou1,3*, Stephanie Santiago1,2, Victoria Garbitt1,2, Ole V. Gjoerup4, J. Dirk Iglehart1,3, Alexander Miron1,3, Andrea L. Richardson1,3, William C. Hahn5,6,7{dagger}, and Jean J. Zhao1,2,3{dagger}

1 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
2 Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
3 Department of Surgery, Brigham and Women’s Hospital, Boston, MA 02115, USA.
4 Molecular Virology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
5 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
6 Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
7 Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.

* 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.

{dagger} To whom correspondence should be addressed. E-mail:jean_zhao{at} (J.J.Z) and william_hahn{at} (W.C.H.)

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, J. J. Zhao, SIK1 Couples LKB1 to p53-Dependent Anoikis and Suppresses Metastasis. Sci. Signal. 2, ra35 (2009).

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