ZNF468-mediated epigenetic upregulation of VEGF-C facilitates lymphangiogenesis and lymphatic metastasis in ESCC via PI3K/Akt and ERK1/2 signaling pathways
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View abstract on PubMed
Summary
This summary is machine-generated.Zinc-finger protein ZNF468 promotes esophageal squamous cell carcinoma (ESCC) lymphangiogenesis and metastasis by epigenetically upregulating VEGF-C. Targeting ZNF468 or its downstream effectors offers potential therapeutic strategies for ESCC patients.
Area Of Science
- Oncology
- Molecular Biology
- Epigenetics
Background
- Dysfunctional lymphangiogenesis is critical in tumor metastasis, particularly in esophageal squamous cell carcinoma (ESCC), impacting treatment outcomes.
- Understanding the molecular drivers of lymphangiogenesis and metastasis in ESCC is essential for developing effective therapies.
Purpose Of The Study
- To investigate the role and molecular mechanisms of Zinc-finger protein 468 (ZNF468) in lymphangiogenesis and lymphatic metastasis in ESCC.
- To explore the clinical relevance of ZNF468 as a prognostic biomarker in ESCC.
Main Methods
- Immunohistochemistry, Western blot, and Kaplan-Meier analysis to correlate ZNF468 expression with ESCC prognosis and lymphangiogenesis.
- In vitro (tube formation, 3D-culture, invasion assays) and in vivo (foot-pads lymph node metastasis model) experiments to assess ZNF468's functional impact.
- CUT&Tag, immunoprecipitation, mass spectrometry, and ChIP-PCR to elucidate ZNF468's epigenetic regulatory mechanisms.
Main Results
- Ectopic ZNF468 expression correlated with increased microlymphatic vessel density and poorer prognosis in ESCC patients.
- ZNF468 significantly enhanced lymphangiogenesis and promoted lymphatic metastasis in ESCC, effects reversed by ZNF468 silencing.
- ZNF468 epigenetically upregulates VEGF-C by recruiting PRMT1/HAT1 to modify histones (H4R2me2a, H3K9ac) on the VEGF-C promoter, requiring PI3K/AKT and ERK1/2 signaling.
- Inhibition of PRMT1 or silencing of VEGF-C abrogated ZNF468-induced lymphatic metastasis.
- Clinical relevance of ZNF468 and VEGF-C was confirmed in ESCC and other cancer types.
Conclusions
- ZNF468 epigenetically upregulates VEGF-C, promoting lymphangiogenesis and lymph node metastasis in ESCC.
- ZNF468 serves as a potential prognostic biomarker and therapeutic target for ESCC.
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