Basal cell carcinoma (BCC), the most common human cancer, results from aberrant activation of the Hedgehog signaling pathway1. Although most cases of BCC are sporadic, some forms are inherited, such as Bazex–Dupré–Christol syndrome (BDCS)—a cancer-prone genodermatosis with an X-linked, dominant inheritance pattern2. We have identified mutations in the ACTRT1 gene, which encodes actin-related protein T1 (ARP-T1), in two of the six families with BDCS that were examined in this study. High-throughput sequencing in the four remaining families identified germline mutations in noncoding sequences surrounding ACTRT1. These mutations were located in transcribed sequences encoding enhancer RNAs (eRNAs)3,4,5 and were shown to impair enhancer activity and ACTRT1 expression. ARP-T1 was found to directly bind to the GLI1 promoter, thus inhibiting GLI1 expression, and loss of ARP-T1 led to activation of the Hedgehog pathway in individuals with BDCS. Moreover, exogenous expression of ACTRT1 reduced the in vitro and in vivo proliferation rates of cell lines with aberrant activation of the Hedgehog signaling pathway. In summary, our study identifies a disease mechanism in BCC involving mutations in regulatory noncoding elements and uncovers the tumor-suppressor properties of ACTRT1.
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The authors wish to thank P. Guigue, A. Vincent-Salomon, L. Fuhrmann, M. Oufadem, S. Thomas, S. Petit, F. Mouchrik, V. Geoffroy, A. Julien, O. Duchamp de Lageneste, L. Galmiche-Rolland, J. Cottineau, J. Rossignol, S. Saunier and D. Pouly for technical assistance and advice; M. Sahbatou for performing linkage analysis; M.-E. Huang for providing cell lines for this study; A. Schmitt and J.-M. Masse at the Cochin Imaging Facility (CNRS UMR 8104) for their assistance and help with transmission electron microscopy; C. Bole-Feysot at the Genomic Platform of IMAGINE Institute for acquiring transcriptomic data; M. Garfa-Traoré, N. Goudin and R. Desvaux at the Cell Imaging Platform of IMAGINE Institute for technical assistance and advice; P. Guigue-Rodet and V. Martin-Bouret for providing skin biopsies from some individuals with BDCS; and M.-C. Hors-Cayla and J.-L. Bonafé for initiating genetic research on BDCS. We are grateful to all subjects and their families for their participation in the study. H.E. was supported by TUBITAK (grant no. 112S398). H.-S.P., E.C., F.K., D.B., M.H. and D.H. were supported by the Swiss National Science Foundation, the Placide Nicod Foundation and the Dind Cottier Foundation. This work was funded by the Association pour la Recherche contre le Cancer and the Société Française de Dermatologie. This work was supported by funding from the Agence Nationale de la Recherche (ANR-10-IAHU-01).