INTU is essential for oncogenic Hh signaling through regulating primary cilia formation in basal cell carcinoma
Authors
Yang, N.Leung, E. L.-H.
Liu, C.
Li, L.
Eguether, Thibaut
Jun Yao, X.-J.
Jones, E. C.
Norris, D. A.
Liu, A.
Clark, R. A.
Roop, D. R.
Pazour, Gregory J.
Shroyer, K. R.
Chen, J.
UMass Chan Affiliations
Program in Molecular MedicineDocument Type
Journal ArticlePublication Date
2017-08-31Keywords
Basal cell carcinomaDiagnostic markers
Morphogen signalling
Transcription
INTU
BCC
cilia
hedgehog
skin
keratinocyte
Cancer Biology
Cell Biology
Developmental Biology
Metadata
Show full item recordAbstract
Inturned (INTU), a cilia and planar polarity effector, performs prominent ciliogenic functions during morphogenesis, such as in the skin. INTU is expressed in adult tissues but its role in tissue maintenance is unknown. Here, we report that the expression of the INTU gene is aberrantly elevated in human basal cell carcinoma (BCC), coinciding with increased primary cilia formation and activated hedgehog (Hh) signaling. Disrupting Intu in an oncogenic mutant Smo (SmoM2)-driven BCC mouse model prevented the formation of BCC through suppressing primary cilia formation and Hh signaling, suggesting that Intu performs a permissive role during BCC formation. INTU is essential for intraflagellar transport A complex assembly during ciliogenesis. To further determine whether Intu is directly involved in the activation of Hh signaling downstream of ciliogenesis, we examined the Hh signaling pathway in mouse embryonic fibroblasts, which readily responds to the Hh pathway activation. Depleting Intu blocked Smo agonist-induced Hh pathway activation, whereas the expression of Gli2DeltaN, a constitutively active Gli2, restored Hh pathway activation in Intu-deficient cells, suggesting that INTU functions upstream of Gli2 activation. In contrast, overexpressing Intu did not promote ciliogenesis or Hh signaling. Taken together, data obtained from this study suggest that INTU is indispensable during BCC tumorigenesis and that its aberrant upregulation is likely a prerequisite for primary cilia formation during Hh-dependent tumorigenesis.Source
Oncogene. 2017 Aug 31;36(35):4997-5005. doi: 10.1038/onc.2017.117. Epub 2017 May 1. Link to article on publisher's site
DOI
10.1038/onc.2017.117Permanent Link to this Item
http://hdl.handle.net/20.500.14038/40430PubMed ID
28459465Related Resources
ae974a485f413a2113503eed53cd6c53
10.1038/onc.2017.117