Recurrent ZC3H18 mutations stabilize oncogenic endogenous retroviral RNA [A375_ribominus]

Endogenous retroviral (ERV) RNA is highly expressed in cancer, although the molecular causes and consequences remain unknown. In multiple cancer types, we identified recurrent truncating mutations in ZC3H18 (Z18), a nuclear RNA surveillance component. We show that Z18 truncating (Z18trunc) mutations are oncogenic and that Z18 plays an evolutionarily conserved role in nuclear RNA surveillance of oncogenic ERV RNA. In zebrafish, Z18trunc accelerated melanoma onset and selectively increased ERV RNA. Z18 mutant human cell lines from the Cancer Cell Line Encyclopedia, TCGA melanoma, and TCGA uterine cancer patient samples also expressed higher levels of ERV RNA. In engineered human melanoma cells, Z18trunc enhanced ERV RNA accumulation more than loss of one Z18 allele, indicating dominant negative activity. In human melanoma cells, Z18trunc directly bound to and stabilized ERV RNA in the cytoplasm. Expression of zebrafish and human Z18-regulated ERV RNA was sufficient to accelerate melanoma in zebrafish. Z18-regulated ERV RNA was required for Z18trunc melanocyte development in zebrafish and for human melanoma cell growth. Our work suggests that ERV RNA, the most highly expressed transposable element RNA in cancer, promotes melanoma and potentially other cancers. This work illuminates a mechanism for elevated ERV transcripts in cancer and supports that aberrant RNA accumulation is broadly oncogenic.