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

Elodie Bal, Hyun Sook Park, Zakia Belaid-Choucair, Hülya Kayserili, Magali Naville, Marine Madrange, Elena Chiticariu, Smail Hadj-Rabia, Nicolas Cagnard, Francois Kuonen, Daniel Bachmann, Marcel Huber, Cindy Le Gall, Francine Côté, Sylvain Hanein, Rasim Özgür Rosti, Ayca Dilruba Aslanger, Quinten Waisfisz, Christine Bodemer, Olivier Hermine & 17 others Fanny Morice-Picard, Bruno Labeille, Frédéric Caux, Juliette Mazereeuw-Hautier, Nicole Philip, Nicolas Levy, Alain Taieb, Marie Françoise Avril, Denis J. Headon, Gabor Gyapay, Thierry Magnaldo, Sylvie Fraitag, Hugues Roest Crollius, Pierre Vabres, Daniel Hohl, Arnold Munnich, Asma Smahi

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)1226-1233
Number of pages8
JournalNature Medicine
Volume23
Issue number10
DOIs
Publication statusPublished - 1 Oct 2017

Cite this

Bal, E., Park, H. S., Belaid-Choucair, Z., Kayserili, H., Naville, M., Madrange, M., ... Smahi, A. (2017). Mutations in ACTRT1 and its enhancer RNA elements lead to aberrant activation of Hedgehog signaling in inherited and sporadic basal cell carcinomas. Nature Medicine, 23(10), 1226-1233. https://doi.org/10.1038/nm.4368
Bal, Elodie ; Park, Hyun Sook ; Belaid-Choucair, Zakia ; Kayserili, Hülya ; Naville, Magali ; Madrange, Marine ; Chiticariu, Elena ; Hadj-Rabia, Smail ; Cagnard, Nicolas ; Kuonen, Francois ; Bachmann, Daniel ; Huber, Marcel ; Le Gall, Cindy ; Côté, Francine ; Hanein, Sylvain ; Rosti, Rasim Özgür ; Aslanger, Ayca Dilruba ; Waisfisz, Quinten ; Bodemer, Christine ; Hermine, Olivier ; Morice-Picard, Fanny ; Labeille, Bruno ; Caux, Frédéric ; Mazereeuw-Hautier, Juliette ; Philip, Nicole ; Levy, Nicolas ; Taieb, Alain ; Avril, Marie Françoise ; Headon, Denis J. ; Gyapay, Gabor ; Magnaldo, Thierry ; Fraitag, Sylvie ; Crollius, Hugues Roest ; Vabres, Pierre ; Hohl, Daniel ; Munnich, Arnold ; Smahi, Asma. / Mutations in ACTRT1 and its enhancer RNA elements lead to aberrant activation of Hedgehog signaling in inherited and sporadic basal cell carcinomas. In: Nature Medicine. 2017 ; Vol. 23, No. 10. pp. 1226-1233.
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title = "Mutations in ACTRT1 and its enhancer RNA elements lead to aberrant activation of Hedgehog signaling in inherited and sporadic basal cell carcinomas",
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-Dupr{\'e}-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.",
author = "Elodie Bal and Park, {Hyun Sook} and Zakia Belaid-Choucair and H{\"u}lya Kayserili and Magali Naville and Marine Madrange and Elena Chiticariu and Smail Hadj-Rabia and Nicolas Cagnard and Francois Kuonen and Daniel Bachmann and Marcel Huber and {Le Gall}, Cindy and Francine C{\^o}t{\'e} and Sylvain Hanein and Rosti, {Rasim {\"O}zg{\"u}r} and Aslanger, {Ayca Dilruba} and Quinten Waisfisz and Christine Bodemer and Olivier Hermine and Fanny Morice-Picard and Bruno Labeille and Fr{\'e}d{\'e}ric Caux and Juliette Mazereeuw-Hautier and Nicole Philip and Nicolas Levy and Alain Taieb and Avril, {Marie Fran{\cc}oise} and Headon, {Denis J.} and Gabor Gyapay and Thierry Magnaldo and Sylvie Fraitag and Crollius, {Hugues Roest} and Pierre Vabres and Daniel Hohl and Arnold Munnich and Asma Smahi",
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Bal, E, Park, HS, Belaid-Choucair, Z, Kayserili, H, Naville, M, Madrange, M, Chiticariu, E, Hadj-Rabia, S, Cagnard, N, Kuonen, F, Bachmann, D, Huber, M, Le Gall, C, Côté, F, Hanein, S, Rosti, RÖ, Aslanger, AD, Waisfisz, Q, Bodemer, C, Hermine, O, Morice-Picard, F, Labeille, B, Caux, F, Mazereeuw-Hautier, J, Philip, N, Levy, N, Taieb, A, Avril, MF, Headon, DJ, Gyapay, G, Magnaldo, T, Fraitag, S, Crollius, HR, Vabres, P, Hohl, D, Munnich, A & Smahi, A 2017, 'Mutations in ACTRT1 and its enhancer RNA elements lead to aberrant activation of Hedgehog signaling in inherited and sporadic basal cell carcinomas' Nature Medicine, vol. 23, no. 10, pp. 1226-1233. https://doi.org/10.1038/nm.4368

Mutations in ACTRT1 and its enhancer RNA elements lead to aberrant activation of Hedgehog signaling in inherited and sporadic basal cell carcinomas. / Bal, Elodie; Park, Hyun Sook; Belaid-Choucair, Zakia; Kayserili, Hülya; Naville, Magali; Madrange, Marine; Chiticariu, Elena; Hadj-Rabia, Smail; Cagnard, Nicolas; Kuonen, Francois; Bachmann, Daniel; Huber, Marcel; Le Gall, Cindy; Côté, Francine; Hanein, Sylvain; Rosti, Rasim Özgür; Aslanger, Ayca Dilruba; Waisfisz, Quinten; Bodemer, Christine; Hermine, Olivier; Morice-Picard, Fanny; Labeille, Bruno; Caux, Frédéric; Mazereeuw-Hautier, Juliette; Philip, Nicole; Levy, Nicolas; Taieb, Alain; Avril, Marie Françoise; Headon, Denis J.; Gyapay, Gabor; Magnaldo, Thierry; Fraitag, Sylvie; Crollius, Hugues Roest; Vabres, Pierre; Hohl, Daniel; Munnich, Arnold; Smahi, Asma.

In: Nature Medicine, Vol. 23, No. 10, 01.10.2017, p. 1226-1233.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Mutations in ACTRT1 and its enhancer RNA elements lead to aberrant activation of Hedgehog signaling in inherited and sporadic basal cell carcinomas

AU - Bal, Elodie

AU - Park, Hyun Sook

AU - Belaid-Choucair, Zakia

AU - Kayserili, Hülya

AU - Naville, Magali

AU - Madrange, Marine

AU - Chiticariu, Elena

AU - Hadj-Rabia, Smail

AU - Cagnard, Nicolas

AU - Kuonen, Francois

AU - Bachmann, Daniel

AU - Huber, Marcel

AU - Le Gall, Cindy

AU - Côté, Francine

AU - Hanein, Sylvain

AU - Rosti, Rasim Özgür

AU - Aslanger, Ayca Dilruba

AU - Waisfisz, Quinten

AU - Bodemer, Christine

AU - Hermine, Olivier

AU - Morice-Picard, Fanny

AU - Labeille, Bruno

AU - Caux, Frédéric

AU - Mazereeuw-Hautier, Juliette

AU - Philip, Nicole

AU - Levy, Nicolas

AU - Taieb, Alain

AU - Avril, Marie Françoise

AU - Headon, Denis J.

AU - Gyapay, Gabor

AU - Magnaldo, Thierry

AU - Fraitag, Sylvie

AU - Crollius, Hugues Roest

AU - Vabres, Pierre

AU - Hohl, Daniel

AU - Munnich, Arnold

AU - Smahi, Asma

PY - 2017/10/1

Y1 - 2017/10/1

N2 - 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.

AB - 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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U2 - 10.1038/nm.4368

DO - 10.1038/nm.4368

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EP - 1233

JO - Nature Medicine

JF - Nature Medicine

SN - 1078-8956

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