Cisplatin-based neoadjuvant chemotherapy has been shown to improve survival in patients with squamous cell carcinoma (SCC), but clinical biomarkers to predict chemosensitivity remain elusive. Here, we show the long noncoding RNA (lncRNA) LINC01011, which we termed cisplatin-sensitivity-associated lncRNA (CISAL), controls mitochondrial fission and cisplatin sensitivity by inhibiting BRCA1 transcription in tongue SCC (TSCC) models. Mechanistically, we found CISAL directly binds the BRCA1 promoter and forms an RNA-DNA triplex structure, sequestering BRCA1 transcription factor-GABPA away from the downstream regulatory binding region. Importantly, the clinical relevance of these findings is suggested by the significant association of CISAL and BRCA1 expression levels in TSCC tumors with neoadjuvant chemosensitivity and overall survival. We propose a new model where lncRNAs are tethered at gene promoter by RNA-DNA triplex formation, spatially sequestering transcription factors away from DNA-binding sites. Our study uncovers the potential of CISAL-BRCA1 signaling as a potential target to predict or improve chemosensitivity.

已显示基于顺铂的新辅助化疗可改善鳞状细胞癌（SCC）患者的生存率，但预测化学敏感性的临床生物标志物仍然难以捉摸。在这里，我们显示了长的非编码RNA（lncRNA）LINC01011，我们称其为顺铂敏感性相关的lncRNA（CISAL），可通过抑制舌癌SCC（TSCC）模型中的BRCA1转录来控制线粒体分裂和顺铂敏感性。从机理上讲，我们发现CISAL直接结合BRCA1启动子并形成RNA-DNA三链体结构，将BRCA1转录因子GABPA隔离在下游的调控结合区之外。重要的是，这些发现的临床相关性由TSCC肿瘤中CISAL和BRCA1表达水平与新辅助化学敏感性和整体生存率之间的显着相关性暗示。我们提出了一个新的模型，其中lncRNA通过RNA-DNA三链体形成束缚在基因启动子上，将转录因子从DNA结合位点空间隔离。我们的研究发现了CISAL-BRCA1信号作为预测或改善化学敏感性的潜在靶标的潜力。