Xu Jinyun, Koch Jonas, Schmidt Claudia, Nientiedt Malin, Neuberger Manuel, Erben Philipp, Michel Maurice Stephan, Rodríguez-Paredes Manuel, Lyko Frank
Division of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research Center, 69120, Heidelberg, Germany.
Core Facility Unit Light Microscopy, German Cancer Research Center, 69120, Heidelberg, Germany.
Exp Mol Med. 2025 Feb;57(1):118-130. doi: 10.1038/s12276-024-01377-x. Epub 2025 Jan 1.
Bladder cancer poses significant clinical challenges due to its high metastatic potential and poor prognosis, especially when it progresses to muscle-invasive stages. Here, we show that the mA reader YTHDC1 is downregulated in muscle-invasive bladder cancer and is negatively correlated with the expression of epithelial‒mesenchymal transition genes. The functional inhibition or depletion of YTHDC1 increased the migration and invasion of urothelial cells. Integrative analysis of multimodal sequencing datasets provided detailed insights into the molecular mechanisms mediating YTHDC1-dependent phenotypes and identified SMAD6 as a key transcript involved in the invasiveness of urothelial carcinoma of the bladder. Notably, SMAD6 mRNA colocalized less with YTHDC1 in tumoral tissues than in paratumoral tissues, indicating disrupted binding during cancer progression. Our findings establish YTHDC1-dependent mA reading as a critical epitranscriptomic mechanism regulating bladder cancer invasiveness and provide a paradigm for the epitranscriptomic deregulation of cancer-associated networks.
膀胱癌因其高转移潜能和不良预后而带来重大临床挑战，尤其是当它进展到肌层浸润阶段时。在此，我们表明mA阅读器YTHDC1在肌层浸润性膀胱癌中表达下调，且与上皮-间质转化基因的表达呈负相关。YTHDC1的功能抑制或缺失增加了尿路上皮细胞的迁移和侵袭。对多模态测序数据集的综合分析为介导YTHDC1依赖性表型的分子机制提供了详细见解，并确定SMAD6是参与膀胱尿路上皮癌侵袭性的关键转录本。值得注意的是，与癌旁组织相比，SMAD6 mRNA在肿瘤组织中与YTHDC1的共定位较少，表明在癌症进展过程中结合被破坏。我们的研究结果确立了依赖YTHDC1的mA阅读作为调节膀胱癌侵袭性的关键表观转录组学机制，并为癌症相关网络的表观转录组失调提供了一个范例。
