Patients with bladder cancer (BCa) frequently acquires resistance to platinum-based chemotherapy, particularly cisplatin. This study centered on the mechanism of cisplatin resistance in BCa and highlighted the pivotal role of lactylation in driving this phenomenon. Utilizing single-cell RNA sequencing, we delineated the single-cell landscape of Bca, pinpointing a distinctive subset of BCa cells that exhibit marked resistance to cisplatin with association with glycolysis metabolism. Notably, we observed that H3 lysine 18 lactylation (H3K18la) plays a crucial role in activating the transcription of target genes by enriching in their promoter regions. Targeted inhibition of H3K18la effectively restored cisplatin sensitivity in these cisplatin-resistant epithelial cells. Furthermore, H3K18la-driven key transcription factors YBX1 and YY1 promote cisplatin resistance in BCa. These findings enhance our understanding of the mechanisms underlying cisplatin resistance, offering valuable insights for identifying novel intervention targets to overcome drug resistance in Bca.

中文翻译：

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单细胞转录组分析揭示了膀胱癌中组蛋白乳酰化与顺铂耐药之间的关联

膀胱癌 (BCa) 患者经常会对铂类化疗产生耐药性，尤其是顺铂。这项研究以 BCa 顺铂耐药机制为中心，并强调了乳酰化在驱动这一现象中的关键作用。利用单细胞 RNA 测序，我们描绘了 Bca 的单细胞景观，精确定位了 BCa 细胞的一个独特子集，这些细胞表现出与糖酵解代谢相关的对顺铂的显着耐药性。值得注意的是，我们观察到 H3 赖氨酸 18 乳酰化 (H3K18la) 通过富集靶基因的启动子区域，在激活靶基因的转录中发挥着至关重要的作用。H3K18la 的靶向抑制有效恢复了这些顺铂耐药上皮细胞的顺铂敏感性。此外，H3K18la 驱动的关键转录因子 YBX1 和 YY1 促进 BCa 中的顺铂耐药。这些发现增强了我们对顺铂耐药机制的理解，为确定新的干预目标以克服 Bca 耐药性提供了宝贵的见解。