Background Aberrant Wnt pathway activation is a key driver of colorectal cancer (CRC) and is essential to sustain tumour growth and progression. Although the downstream protein-coding target genes of the Wnt cascade are well known, the long non-coding transcriptome has not yet been fully resolved. Objective In this study, we aim to comprehensively reveal the Wnt-regulated long non-coding transcriptome and exploit essential molecules as novel therapeutic targets. Design We used global run-on sequencing to define β-catenin-regulated long non-coding RNAs (lncRNAs) in CRC. CRISPRi dropout screens were subsequently used to establish the functional relevance of a subset of these lncRNAs for long-term expansion of CRC. Results We uncovered that LINC02418 is essential for cancer cell clonogenic outgrowth. Mechanistically, LINC02418 regulates MYC expression levels to promote CRC stem cell functionality and prevent terminal differentiation. Furthermore, we developed effective small interfering RNA (siRNA)-based therapeutics to target LINC02418 RNA in vivo . Conclusion We propose that cancer-specific Wnt-regulated lncRNAs provide novel therapeutic opportunities to interfere with the Wnt pathway, which has so far defied effective pharmacological inhibition. Data are available in a public, open access repository. All data relevant to the study are included in the article or uploaded as supplementary information. The sequence libraries generated in this study are publicly available through the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) under accession code: GSE206582.

中文翻译：

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识别 Wnt 驱动的长链非编码转录组中的结直肠癌特异性脆弱性


背景 异常的 Wnt 通路激活是结直肠癌 （CRC） 的关键驱动因素，对于维持肿瘤生长和进展至关重要。尽管 Wnt 级联反应的下游蛋白质编码靶基因是众所周知的，但长链非编码转录组尚未完全解析。目的 本研究旨在全面揭示 Wnt 调控的长链非编码转录组，并将必需分子作为新的治疗靶点。设计我们使用全局运行测序来定义 CRC 中 β-catenin 调节的长链非编码 RNA （lncRNA）。随后使用 CRISPRi 缺失筛选来确定这些 lncRNA 子集与 CRC 长期扩增的功能相关性。结果 我们发现 LINC02418 对于癌细胞克隆形成生长至关重要。从机制上讲，LINC02418调节 MYC 表达水平以促进 CRC 干细胞功能并防止终末分化。此外，我们开发了有效的基于小干扰 RNA （siRNA） 的治疗方法，以靶向体内LINC02418 RNA。结论 我们提出癌症特异性 Wnt 调节的 lncRNAs 为干扰 Wnt 通路提供了新的治疗机会，该通路迄今为止一直无法有效药理学抑制。数据在公共、开放访问存储库中可用。与研究相关的所有数据都包含在文章中或作为补充信息上传。本研究中生成的序列文库可通过美国国家生物技术信息中心 （NCBI） 基因表达综合 （GEO） 公开获得，登录代码为 GSE206582。