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Published on: July 20, 2019
FOXN3 Regulates Autophagic Activity to Suppress Drug Resistance in Melanoma Cells
Yaqi Wang1,2, Hui Su1, Xiaopeng Wang1
1Department of Dermatology, Xi'an Jiaotong University The Second Affiliated Hospital, Xi'an, Shaanxi, People's Republic of China.
Background:
The forkhead box (FOX) family member FOXN3 has been reported to inhibit transcriptional activity associated with regulating tumor development. However, the role of FOXN3 in the pathogenesis of melanoma is not well understood.
Objective:
To investigate the biological functions of FOXN3 in drug resistance of melanoma.
Materials And Methods:
The expression of FOXN3 in melanoma was investigated using Gene Expression profiling interactive analysis (GEPIA) and Linkedomics databases. Melanoma cell proliferation, invasion, and migration were assessed using the colony formation assay, the scratch wound healing test, the Transwell invasion assay, and the nude mice xenograft to determine the effects of FOXN3 over-expression and depletion. The functional role of the transcriptional regulator in melanoma cells was tested through chromatin immunoprecipitation, immunofluorescence.
Results:
FOXN3 was downregulated in melanoma. Over-expression of FOXN3 inhibited the proliferation and motility of melanoma cells, whereas FOXN3 knockdown significantly enhanced the proliferation and motility of melanoma cells. Overexpression of FOXN3 reduced autophagic activity in melanoma cells. Enhanced autophagic activity in drug-resistant melanoma cell lines is related to drug-sensitive cells, and significant differences in FOXN3 localization were observed when comparing melanoma cells that were sensitive and resistant to Vemurafenib. Additionally, FOXN3 has been identified as binding to the promoter region of the cancer antigen Fibrous Sheath Interacting Protein 1 (FSIP1), thereby regulating the expression of this gene.
Conclusion:
FOXN3 functions as an important regulator of the development and progression of Vemurafenib-resistant melanoma cells, partly owing to its binding to the FISP1. As such, FOXN3 may represent a relevant target for therapeutic interventions in patients suffering from drug-resistant melanoma.
Insights
Forkhead box N3 (FOXN3) is downregulated in melanoma and inhibits cell proliferation and motility. FOXN3 targets Fibrous Sheath Interacting Protein 1 (FSIP1), making it a potential therapeutic target for drug-resistant melanoma.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Forkhead box N3 (FOXN3) is a transcriptional regulator implicated in tumor development.
- Its specific role in melanoma pathogenesis and drug resistance remains largely uncharacterized.
Purpose of the Study:
- To elucidate the biological functions of FOXN3 in the context of melanoma drug resistance.
- To investigate FOXN3's role in melanoma cell proliferation, motility, and response to Vemurafenib.
Main Methods:
- Gene expression analysis using GEPIA and Linkedomics databases.
- In vitro assays including colony formation, scratch wound healing, and Transwell invasion.
- In vivo xenograft studies in nude mice.
- Chromatin immunoprecipitation and immunofluorescence to assess protein function and localization.
Main Results:
- FOXN3 expression is downregulated in melanoma.
- FOXN3 overexpression suppressed melanoma cell proliferation and motility, while knockdown enhanced them.
- FOXN3 overexpression reduced autophagic activity; drug-resistant cells showed increased autophagy.
- FOXN3 binds to the promoter of Fibrous Sheath Interacting Protein 1 (FSIP1), regulating its expression.
Conclusions:
- FOXN3 is a key regulator in the development of Vemurafenib-resistant melanoma.
- FOXN3's interaction with FSIP1 contributes to its role in drug resistance.
- FOXN3 presents a promising therapeutic target for treating drug-resistant melanoma.
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