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.

中文翻译：

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ACTRT1及其增强子RNA元件的突变导致遗传性和散发性基底细胞癌中刺猬信号的异常激活。

基底细胞癌（BCC）是最常见的人类癌症，是由Hedgehog信号通路的异常激活引起的。尽管大多数BCC病例是散发性的，但还是会遗传一些形式，例如Bazex-Dupré-Christol综合征（BDCS）-一种易患癌症的遗传性皮肤病，具有X连锁的显性遗传模式。我们在本研究中研究的六个BDCS家族中的两个家族中，已经确定了ACTRT1基因的突变，该基因编码肌动蛋白相关蛋白T1（ARP-T1）。其余四个家族的高通量测序确定了ACTRT1周围非编码序列的种系突变。这些突变位于编码增强子RNA（eRNA）的转录序列中，并显示会削弱增强子活性和ACTRT1表达。发现ARP-T1直接与GLI1启动子结合，从而抑制了GLI1的表达，而ARP-T1的缺失会导致BDCS患者的Hedgehog途径活化。此外，ACTRT1的外源表达降低了Hedgehog信号通路异常激活的细胞株的体外和体内增殖速率。总之，我们的研究确定了BCC中涉及调节性非编码元件突变的疾病机制，并揭示了ACTRT1的肿瘤抑制特性。