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

Abstract

Inturned (INTU), a cilia and planar polarity effector (CPLANE), 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 IFT-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 respond to Hh pathway activation. Depleting Intu blocked SAG-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.

Clinical Implications of Primary Cilia in Skin Cancer

“…1a), which transduce HH signals from SMO to GLI2 [60,61]. In fact, in mouse models of BCC, scientists have shown that both the ciliary gene Intu and HH signaling are necessary for BCC tumorigenesis and progression [61,62]. Thus, the primary cilium, through HH signaling, acts a crucial nexus in the pathogenesis of BCC.…”

Mixed signals from the cell's antennae: primary cilia in cancer

“…Concurring with the established link between PC and Hh signaling, expression of PC has been found in biopsies of BCC patients and skin lesions in mice constitutively expressing active Smo . A more recent study reported abundant ciliated keratinocytes in BCC specimens in comparison with healthy skin and biopsies of squamous cell carcinoma (SCC), another form of skin cancer . To explore the role of PC and Hh in BCC, Wong and colleagues used an approach similar to the one described by Han el al in their study on medulloblastoma (see above).…”

“…Primary cilia formation and Hh signaling in BCC were found to be regulated by inturned (INTU), a cilia and planar polarity effector protein . INTU expression was found to be elevated in biopsies of BCC, as compared to those of SCC patients and healthy donors and correlated with the presence of PC.…”

“…However, the improvement of reagents and techniques for the detection of PC showed that PC can be also present in cancer cells . Today, a growing body of work demonstrates that transformed cells are capable of retaining the ability to form cilia even in culture without serum starvation .…”

The regulation of cilium assembly and disassembly in development and disease

“…Similarly, the loss of cilia protects mice from tumorigenesis in a basal cell carcinoma model driven by constitutively active SmoM2 (Wong et al, 2009). In this context, the expression of inturned (Intu), a planar cell polarity effector required for cilium assembly that regulates apical actin networks, is aberrantly elevated, whereas disruption of Intu prevents the formation of basal cell carcinoma by suppressing primary cilia formation and Hh signaling (Yang et al, 2017).…”