Title

INTU is essential for oncogenic Hh signaling through regulating primary cilia formation in basal cell carcinoma

UMMS Affiliation

Program in Molecular Medicine

Publication Date

8-31-2017

Document Type

Article

Disciplines

Cancer Biology | Cell Biology | Developmental Biology

Abstract

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.

Keywords

Basal cell carcinoma, Diagnostic markers, Morphogen signalling, Transcription, INTU, BCC, cilia, hedgehog, skin, keratinocyte

DOI of Published Version

10.1038/onc.2017.117

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

Journal/Book/Conference Title

Oncogene

Related Resources

Link to Article in PubMed

PubMed ID

28459465