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

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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 Gli2ΔN, 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.

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Acknowledgements

We thank Stephanie Burke and Mallory Korman for histology assistance. This study is supported by the Research Histology Core Laboratory of the Department of Pathology, the Cancer Center of Stony Brook University, and research grants from NIH (AR061485 to JC; AR060388 and CA052607 to DRR), a Young Investigator Career Development Award from the PKD foundation (02YI08A to AL), a Pilot and Feasibility Award from the SDRC of University of Colorado Denver (NIH, AR057212), and the REACH program of Stony Brook University (NIH, U01HL127522 and the NYS Department of Economic Development, C140151).

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Correspondence to J Chen.

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