ACTRT1 Inhibits Hedgehog Signaling to Suppress Basal Cell Carcinoma

The majority of basal cell carcinomas (BCC) exhibit aberrant constitutive activation of Hedgehog signaling. Although most BCCs are sporadic, BCC can also be inherited, as in Bazex–Dupré–Christol syndrome (BDCS), an X-linked condition that predisposes to BCC. Bal and colleagues discovered an insertion in ACTRT1 [which encodes actin-related protein T1 (ARP-T1)] that resulted in a truncated protein in two of six families with BDCS. The other four families lacked coding rearrangements in ACTRT1, but harbored germline mutations in conserved enhancer regions that led to reduced ACTRT1 expression. ARP-T1 expression was absent in tumor tissue from 51 of 60 patients with sporadic BCC, and sequencing of 20 BCC samples identified a subset of patients with coding or enhancer mutations in ACTRT1, suggesting that ACTRT1 mutations may occur in sporadic BCC as well as inherited BCC. Transcriptomic analyses found that individuals with BDCS had deregulated expression of genes involved in the regulation of cell-cycle progression, cell death and survival, and cell migration. Further, target genes of the Hedgehog transcription factors GLI1 and GLI2 were overexpressed in patients with ACTRT1-mutant BDCS. Mechanistically, full length ARP-T1, but not the truncated protein, bound directly to the GLI1 promoter to repress GLI1 transcription and prevent expression of Hedgehog target genes. Consistent with these findings, exogenous expression of wild-type ARP-T1 suppressed BCC cell growth in vitro and in vivo and reduced expression of GLI1/2, suggesting a tumor suppressive role for ACTRT1 in BCC in reducing Hedgehog signaling. Additionally, ARP-T1 overexpression suppressed the growth of breast cancer and osteosarcoma cell lines with aberrant Hedgehog signaling. In addition to identifying ACTRT1 as a tumor suppressor gene whose disruption promotes aberrant Hedgehog signaling to drive inherited and sporadic BCC, these findings suggest that ACTRT1 expression may also suppress the growth of other tumor types driven by aberrant Hedgehog signaling.

Bal E, Park HS, Belaid-Choucair Z, Kayserili H, Naville M, Madrange M, et al. 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 Sep 4 [Epub ahead of print].

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