Genome-wide RNAi screen reveals disease-associated genes that are common to Hedgehog and Wnt signaling

Leni S. Jacob, Xiaofeng Wu, Michael E. Dodge, Chih Wei Fan, Ozlem Kulak, Baozhi Chen, Wei Tang, Baolin Wang, James F. Amatruda, Lawrence Lum

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article numberra4
JournalScience Signaling
Volume4
Issue number157
DOIs
StatePublished - Jan 25 2011

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Hedgehogs
RNA Interference
Genes
Genome
Wnt Signaling Pathway
Cilia
Tissue
Acyltransferases
Multitasking
Signal transduction
Histone Deacetylases
Porcupines
Tubulin
Tumors
Screening
Phosphotransferases
Cells
Uterine Cervical Neoplasms
RNA
Embryonic Development

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Genome-wide RNAi screen reveals disease-associated genes that are common to Hedgehog and Wnt signaling. / Jacob, Leni S.; Wu, Xiaofeng; Dodge, Michael E.; Fan, Chih Wei; Kulak, Ozlem; Chen, Baozhi; Tang, Wei; Wang, Baolin; Amatruda, James F.; Lum, Lawrence.

In: Science Signaling, Vol. 4, No. 157, ra4, 25.01.2011.

Research output: Contribution to journalArticle

Jacob, Leni S. ; Wu, Xiaofeng ; Dodge, Michael E. ; Fan, Chih Wei ; Kulak, Ozlem ; Chen, Baozhi ; Tang, Wei ; Wang, Baolin ; Amatruda, James F. ; Lum, Lawrence. / Genome-wide RNAi screen reveals disease-associated genes that are common to Hedgehog and Wnt signaling. In: Science Signaling. 2011 ; Vol. 4, No. 157.
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