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Mutations in ACTRT1 and its transcribed non-coding elements lead to aberrant activation of the Hedgehog signaling pathway 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 as in Bazex-Dupré-Christol syndrome (BDCS), an X-linked, dominant, cancer-prone type of genodermatosis. We discovered mutations in the ACTRT1 gene coding for actin-related protein T1 (Arp-T1) in 2/6 BDCS families. High-throughput sequencing revealed germline mutations in non-coding sequences surrounding ACTRT1 in the remaining four families. These mutations were located in transcribed enhancer regions (eRNA) and impaired enhancer activity and ACTRT1 expression. Furthermore, we found that Arp-T1 directly binds to the Gli1 promoter, thus inhibiting its expression, while loss of Arp-T1 led to activation of Hedgehog pathway in BDCS patients. Moreover, ACTRT1 reduced in vitro and in vivo proliferation of human BCC cell line and two tumor cell lines where Hedgehog signaling pathway is aberrantly activated (MDA-MB231 breast cancer and U2OS osteosarcoma cell lines). Our study highlights a novel causative mechanism in BCCs, demonstrates that ACTRT1 could act as a tumor suppressor beyond the context of BCC, and suggests that ACTRT1 and its regulatory regions may be potential therapeutic targets in cancerology.

ORGANISM(S): Homo sapiens

SUBMITTER: Nicolas Cagnard

PROVIDER: E-MTAB-5597 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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