Super‐Enhancer Driven LIF/LIFR‐STAT3‐SOX2 Regulatory Feedback Loop Promotes Cancer Stemness in Head and Neck Squamous Cell Carcinoma

作者：Jin Li, Y. Andrew Wang, Ziyu Wang, Yuxiang Wei, Pengfei Diao, Yaping Wu, Dongmiao Wang, Hongbing Jiang, Yanling Wang, Jie Cheng · 发表于：Advanced Science · 年份：2024 · DOI：10.1002/advs.202404476 · 被引用次数：25 · 研究领域：Cancer-related molecular mechanisms research、RNA Research and Splicing、RNA modifications and cancer

Super-enhancers (SEs) have been recognized as key epigenetic regulators underlying cancer stemness and malignant traits by aberrant transcriptional control and promising therapeutic targets against human cancers. However, the SE landscape and their roles during head and neck squamous cell carcinoma (HNSCC) development especially in cancer stem cells (CSCs) maintenance remain underexplored yet. Here, we identify leukemia inhibitory factor (LIF)-SE as a representative oncogenic SE to activate LIF transcription in HNSCC. LIF secreted from cancer cells and cancer-associated fibroblasts promotes cancer stemness by driving SOX2 transcription in an autocrine/paracrine manner, respectively. Mechanistically, enhancer elements E1, 2, 4 within LIF-SE recruit SOX2/SMAD3/BRD4/EP300 to facilitate LIF transcription; LIF activates downstream LIFR-STAT3 signaling to drive SOX2 transcription, thus forming a previously unknown regulatory feedback loop (LIF-SE-LIF/LIFR-STAT3-SOX2) to maintain LIF overexpression and CSCs stemness. Clinically, increased LIF abundance in clinical samples correlate with malignant clinicopathological features and patient prognosis; higher LIF concentrations in presurgical plasma dramatically diminish following cancer eradication. Therapeutically, pharmacological targeting LIF-SE-LIF/LIFR-STAT3 significantly impairs tumor growth and reduces CSC subpopulations in xenograft and PDX models. Our findings reveal a hitherto uncharacterized LIF-SE-mediated auto-regulatory lo...