SIK1 couples LKB1 to p53-dependent anoikis and suppresses metastasis.
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.
Cheng
Hailing
H
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Liu
Pixu
P
Wang
Zhigang C
ZC
Zou
Lihua
L
Santiago
Stephanie
S
Garbitt
Victoria
V
Gjoerup
Ole V
OV
Iglehart
J Dirk
JD
Miron
Alexander
A
Richardson
Andrea L
AL
Hahn
William C
WC
Zhao
Jean J
JJ
D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D023102:Anoikis; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D017346:Protein Serine-Threonine Kinases; C509080:SIK1 protein, human; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases