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| Status |
Public on Nov 06, 2024 |
| Title |
Super-enhancer driven LIF/LIFR-STAT3-SOX2 regulatory feedback loop promotes cancer stemness in head and neck squamous cell carcinoma (ChIP-seq) |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
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 identified 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 or paracrine manner, respectively. Mechanistically, enhancer elements E1, 2, 4 within LIF-SE recruited SOX2/SMAD3/BRD4/EP300 to facilitate LIF transcription; LIF activated 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 correlated with malignant clinicopathological features and patient prognosis; higher LIF concentrations in presurgical plasma were negatively associated with patient survival and dramatically diminished following cancer eradication. Therapeutically, pharmacological targeting LIF-SE-LIF/LIFR-STAT3 significantly impaired tumor growth and reduced CSC subpopulations in HNSCC xenograft and PDX models. Our findings reveal a hitherto uncharacterized LIF-SE-mediated auto-regulatory loop in regulating HNSCC stemness and highlight LIF as a novel non-invasive biomarker and potential therapeutic target for HNSCC.
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| Overall design |
BRD4 as well as EP300 ChIP-seq in human head and neck squamous cell carcinoma cell line
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| Contributor(s) |
Li J, Wang Y, Wang Z, Wei Y, Diao P, Wu Y, Wang D, Jiang H, Wang Y, Cheng J |
| Citation(s) |
39206755 |
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| Submission date |
Aug 16, 2024 |
| Last update date |
Nov 07, 2024 |
| Contact name |
Jin Li |
| E-mail(s) |
[email protected]
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| Phone |
+86 85031886
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| Organization name |
Nanjing Medical University
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| Department |
OMFS
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| Street address |
140, Hanzhong Road
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| City |
Nanjing |
| ZIP/Postal code |
210000 |
| Country |
China |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (3) |
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| Relations |
| BioProject |
PRJNA1148921 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE274995_RAW.tar |
458.9 Mb |
(http)(custom) |
TAR (of BW, NARROWPEAK) |
SRA Run Selector |
| Raw data are available in SRA |
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