Tanu Tanzina, Cox Anna M, Karlow Jennifer, Sharma Priyanka, He Xueyang, Wu Constance, Babu Swathy, Brown Jared, Brown Kevin M, Chanock Stephen J, Liu David, Zhang Tongwu, Burns Kathleen H, Boutz Paul L, Insco Megan L
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Department of Pathology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
bioRxiv. 2025 Jan 14:2025.01.10.632423. doi: 10.1101/2025.01.10.632423.
Endogenous retroviral (ERV) RNA is highly expressed in cancer, although the molecular causes and consequences remain unknown. We found that ZC3H18 (Z18), a component of multiple nuclear RNA surveillance complexes, has recurrent truncating mutations in cancer. We show that Z18 mutations are oncogenic and that Z18 plays an evolutionarily conserved role in nuclear RNA surveillance of ERV RNA. In zebrafish, Z18 expedited melanoma onset and promoted a specific accumulation of ERV RNA. Z18 mutant human cell lines from the Cancer Cell Line Encyclopedia also expressed higher levels of ERV RNA. In engineered human melanoma cells, Z18 enhanced ERV RNA accumulation more than loss of one Z18 copy, indicating dominant negative activity. Z18 directly bound and stabilized ERV RNA. Notably, expression of ERV RNA was sufficient to expedite oncogenesis in a zebrafish model, which is the first evidence of which we are aware that ERV transcripts can play a functional role in cancer. Our work illuminates a mechanism for elevated ERV transcripts in cancer and supports that aberrant RNA accumulation is broadly oncogenic.
内源性逆转录病毒（ERV）RNA在癌症中高度表达，但其分子机制及后果仍不清楚。我们发现，ZC3H18（Z18）作为多种核RNA监测复合体的一个组成部分，在癌症中存在反复的截短突变。我们表明，Z18突变具有致癌性，并且Z18在ERV RNA的核RNA监测中发挥着进化上保守的作用。在斑马鱼中，Z18加速了黑色素瘤的发生，并促进了ERV RNA的特异性积累。来自癌症细胞系百科全书的Z18突变人类细胞系也表达了更高水平的ERV RNA。在工程化的人类黑色素瘤细胞中，Z18比缺失一个Z18拷贝更能增强ERV RNA的积累，表明其具有显性负性活性。Z18直接结合并稳定ERV RNA。值得注意的是，ERV RNA的表达足以在斑马鱼模型中加速肿瘤发生，这是我们所知的ERV转录本可在癌症中发挥功能作用的首个证据。我们的研究揭示了癌症中ERV转录本升高的机制，并支持异常RNA积累具有广泛致癌性的观点。
