Forkhead box protein k1 recruits TET1 to act as a tumor suppressor and is associated with MRI detection
Taotao Sun1, Huijuan Wang2, Qiang Li3
1Department of Radiology, International Peace Maternity and Child Health Hospital, Shanghai Jiaotong University, Shanghai.
Objective:
Today, more and more evidence suggests that Foxk proteins (Foxk1 and Foxk2) work as transcriptional repressors in different kinds of cancer, but whether Foxk1 has a role in mediating tumorigenesis in breast cancer, the evidence is rare.
Methods:
MCF-7 cells transfected with shFoxk1 displayed a mesenchymal morphology and reduced the expression of E-cadherin, and increased the expression of N-cadherin. Transwell invasion assay and living imaging assay show that the overexpression of Foxk1 could inhibit metastasis in vitro and in vivo. Ribonucleic acid sequencing revealed that the knockdown of Foxk1 resulted in the up-regulation of different oncogenes, which was implicated in metastasis and tumor angiopoiesis. Quantitative chromatin immunoprecipitation, chromatin immunoprecipitation and Luciferase reporter assays suggested that Foxk1 could bind to the promoter of epithelial-mesenchymal transition inducer Twist and vascular endothelial growth factor, VEGF. Mass Spectrometry, co-immunoprecipitation assays and glutathione-S-transferase pull-down assay detected that Foxk1 was physically associated with Ten-eleven translocation 1, TET1, in vivo and in vitro.
Results:
We reported that the mean expression level of Foxk1 in breast cancer was significantly lower than the adjacent noncarcinoma tissue. The higher Foxk1 expression was associated with better prognosis. Endothelial tube formation assays indicated that Foxk1 might regulate breast cancer angiogenesis through transcriptional repression of vascular endothelial growth factor. Furthermore, in vivo magnetic resonance imaging revealed the overexpression of Foxk1 could enhance the detection of the tumors. Further, a strong negative correlation was observed between Foxk1 and Twsit or between Foxk1 and vascular endothelial growth factor, and the higher Foxk1 expression is correlated with better over all survivals and better relapse-free survivals.
Conclusions:
Together, our data indicated the function of Foxk1 as a tumor suppressor in facilitating angiogenesis and metastasis in breast cancer.
Insights
Foxk1 acts as a tumor suppressor in breast cancer, inhibiting metastasis and angiogenesis. Lower Foxk1 expression correlates with poorer prognosis, suggesting its role in controlling tumor growth and spread.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Foxk proteins (Foxk1 and Foxk2) are increasingly recognized as transcriptional repressors in various cancers.
- Limited evidence exists regarding the specific role of Foxk1 in breast cancer tumorigenesis.
Purpose of the Study:
- To investigate the function of Foxk1 in breast cancer progression, focusing on its role in metastasis and angiogenesis.
- To elucidate the molecular mechanisms by which Foxk1 may exert tumor-suppressive effects in breast cancer.
Main Methods:
- Utilized MCF-7 cells with Foxk1 knockdown and overexpression to assess morphological changes, cell adhesion molecule expression (E-cadherin, N-cadherin), and metastatic potential via Transwell and live imaging assays.
- Employed RNA sequencing to identify genes regulated by Foxk1, focusing on those involved in metastasis and angiogenesis.
- Conducted quantitative ChIP, ChIP-seq, and luciferase reporter assays to determine Foxk1 binding to target gene promoters (Twist, VEGF).
- Investigated Foxk1 protein interactions using Mass Spectrometry, co-immunoprecipitation, and GST pull-down assays to identify binding partners (TET1).
Main Results:
- Foxk1 expression was significantly lower in breast cancer tissues compared to adjacent non-cancerous tissues.
- Higher Foxk1 expression correlated with improved patient prognosis, including overall and relapse-free survival.
- Foxk1 overexpression inhibited endothelial tube formation, suggesting a role in suppressing angiogenesis via repression of vascular endothelial growth factor (VEGF).
- Foxk1 directly binds to the promoters of Twist and VEGF, key regulators of epithelial-mesenchymal transition and angiogenesis.
- Foxk1 physically interacts with Ten-eleven translocation 1 (TET1).
Conclusions:
- Foxk1 functions as a tumor suppressor in breast cancer.
- Foxk1 inhibits angiogenesis and metastasis by repressing key oncogenes like Twist and VEGF.
- Foxk1's interaction with TET1 may contribute to its tumor-suppressive functions.
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