Mutations in ACTRT1 and its enhancer RNA elements lead to aberrant activation of Hedgehog signaling in inherited and sporadic basal cell carcinomas

Nat Med. 2017 Oct;23(10):1226-1233. doi: 10.1038/nm.4368.

Elodie Bal ¹ ², Hyun-Sook Park ³, Zakia Belaid-Choucair ¹ ² ⁴, Hülya Kayserili ⁵ ⁶, Magali Naville ⁷ ⁸ ⁹, Marine Madrange ¹ ², Elena Chiticariu ³, Smail Hadj-Rabia ¹ ² ¹⁰, Nicolas Cagnard ¹¹, Francois Kuonen ³, Daniel Bachmann ³, Marcel Huber ³, Cindy Le Gall ¹ ², Francine Côté ¹ ² ⁴, Sylvain Hanein ¹ ², Rasim Özgür Rosti ⁶ ¹², Ayca Dilruba Aslanger ⁶, Quinten Waisfisz ¹³, Christine Bodemer ¹ ² ¹⁰, Olivier Hermine ¹ ² ⁴ ¹⁴ ¹⁵, Fanny Morice-Picard ¹⁶, Bruno Labeille ¹⁷, Frédéric Caux ¹⁸, Juliette Mazereeuw-Hautier ¹⁹, Nicole Philip ²⁰ ²¹, Nicolas Levy ²⁰ ²¹, Alain Taieb ¹⁶ ²², Marie-Françoise Avril ²³, Denis J Headon ²⁴, Gabor Gyapay ²⁵, Thierry Magnaldo ²⁶, Sylvie Fraitag ²⁷, Hugues Roest Crollius ⁷ ⁸ ⁹, Pierre Vabres ²⁸, Daniel Hohl ³, Arnold Munnich ¹ ², Asma Smahi ¹ ²

Affiliations

1 Paris Descartes University, Sorbonne Paris Cité, Paris, France.
2 IMAGINE Institute, INSERM UMR 1163, Paris, France.
3 Department of Dermatology, Lausanne University Hospital, Hôpital de Beaumont, Lausanne, Switzerland.
4 Department of Hematology, Hôpital Necker-Enfants Malades, Paris, France.
5 Medical Genetics Department, Koç University School of Medicine (KUSOM), Istanbul, Turkey.
6 Medical Genetics Department, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey.
7 Institut de Biologie de l'ENS (IBENS), École Normale Supérieure, Paris, France.
8 CNRS, UMR 8197, Paris, France.
9 INSERM U1024, Paris, France.
10 Department of Dermatology, Hôpital Necker-Enfants Malades, Paris, France.
11 Plateforme Bio-informatique, Structure Fédérative de Recherche Necker, INSERM US24/CNRS, UMS 3633, Paris, France.
12 Laboratory of Genome Maintenance, Rockefeller University, New York, New York, USA.
13 Department of Clinical Genetics, Vrije Universiteit Medical Center, Amsterdam, the Netherlands.
14 GR-Ex Laboratory of Excellence, IMAGINE Institute, Paris, France.
15 Centre Référence Nationale pour les Mastocytoses, Hôpital Necker-Enfants Malades, Paris, France.
16 Centre de référence pour les maladies rares de la peau, Service de Dermatologie, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.
17 Department of Dermatology, Centre Hospitalier Universitaire Nord, Saint-Etienne, France.
18 Department of Dermatology, Hôpital Avicenne, Bobigny, France.
19 Department of Dermatology, Centre de Référence des Maladies Rares de la Peau, Hôpital Larrey, Toulouse, France.
20 Department of Medical Genetics, Hôpital de la Timone, Marseille, France.
21 AMU-INSERM, UMR_S910, Faculté de Médecine de Marseille, Marseille, France.
22 INSERM U1035, Université de Bordeaux, Bordeaux, France.
23 Department of Dermatology, Hôpital Cochin, Paris, France.
24 Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh, UK.
25 Genoscope (CEA), CNRS UMR 8030, University of Evry, Evry, France.
26 Institute for Research on Cancer and Aging, CNRS UMR 7284, INSERM U1081, University of Nice Sophia Antipolis, Nice, France.
27 Department of Pathological Anatomy, Hôpital Necker-Enfants Malades, Paris, France.
28 Department of Dermatology, Centre Hospitalier Universitaire, Hôpital du Bocage, Dijon, France.

PMID: 28869610 DOI: 10.1038/nm.4368

Abstract

Basal cell carcinoma (BCC), the most common human Cancer, results from aberrant activation of the Hedgehog signaling pathway. 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 pattern. 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) 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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