Genome-wide RNAi screen reveals disease-associated genes that are common to Hedgehog and Wnt signaling.
The Hedgehog (Hh) and Wnt signal transduction pathways are master regulators of embryogenesis and tissue renewal and represent anticancer therapeutic targets. Using genome-wide RNA interference screening in murine cultured cells, we established previously unknown associations between these signaling pathways and genes linked to developmental malformations, diseases of premature tissue degeneration, and cancer. We identified functions in both pathways for the multitasking kinase Stk11 (also known as Lkb1), a tumor suppressor implicated in lung and cervical cancers. We found that Stk11 loss resulted in disassembly of the primary cilium, a cellular organizing center for Hh pathway components, thus dampening Hh signaling. Loss of Stk11 also induced aberrant signaling through the Wnt pathway. Chemicals that targeted the Wnt acyltransferase Porcupine or that restored primary cilia length by inhibiting the tubulin deacetylase HDAC6 (histone deacetylase 6) countered deviant pathway activities driven by Stk11 loss. Our study demonstrates that Stk11 is a critical mediator in both the Hh and the Wnt pathways, and our approach provides a platform to support the development of targeted therapeutic strategies.
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Leni S
LS
Jacob
Xiaofeng
X
Wu
Michael E
ME
Dodge
Chih-Wei
CW
Fan
Ozlem
O
Kulak
Baozhi
B
Chen
Wei
W
Tang
Baolin
B
Wang
James F
JF
Amatruda
Lawrence
L
Lum
D016475:3T3 Cells; D055372:AMP-Activated Protein Kinases; D000217:Acyltransferases; D000818:Animals; D015153:Blotting, Western; D002923:Cilia / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D005455:Fluorescent Antibody Technique; D055785:Gene Knockdown Techniques; D023281:Genomics; D053823:Hedgehog Proteins / Q000378:metabolism*; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D046529:Microscopy, Electron, Transmission; D009419:Nerve Tissue Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics*; D051153:Wnt Proteins / Q000378:metabolism*; D015027:Zebrafish; D000074290:Zinc Finger Protein Gli3
D017931:DNA Primers; C465571:Gli3 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D051153:Wnt Proteins; D000074290:Zinc Finger Protein Gli3; D000217:Acyltransferases; C491187:Porcn protein, mouse; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases
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