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Published on: December 26, 2016
FOXK2 affects cancer cell response to chemotherapy by promoting nucleotide de novo synthesis
Aims:
Nucleotide de novo synthesis is essential to cell growth and survival, and its dysregulation leads to cancers and drug resistance. However, how this pathway is dysregulated in cancer has not been well clarified. This study aimed to identify the regulatory mechanisms of nucleotide de novo synthesis and drug resistance.
Methods:
By combining the ChIP-Seq data from the Cistrome Data Browser, RNA sequencing (RNA-Seq) and a luciferase-based promoter assay, we identified transcription factor FOXK2 as a regulator of nucleotide de novo synthesis. To explore the biological functions and mechanisms of FOXK2 in cancers, we conducted biochemical and cell biology assays in vitro and in vivo. Finally, we assessed the clinical significance of FOXK2 in hepatocellular carcinoma.
Results:
FOXK2 directly regulates the expression of nucleotide synthetic genes, promoting tumor growth and cancer cell resistance to chemotherapy. FOXK2 is SUMOylated by PIAS4, which elicits FOXK2 nuclear translocation, binding to the promoter regions and transcription of nucleotide synthetic genes. FOXK2 SUMOylation is repressed by DNA damage, and elevated FOXK2 SUMOylation promotes nucleotide de novo synthesis which causes resistance to 5-FU in hepatocellular carcinoma. Clinically, elevated expression of FOXK2 in hepatocellular carcinoma patients was associated with increased nucleotide synthetic gene expression and correlated with poor prognoses for patients.
Conclusion:
Our findings establish FOXK2 as a novel regulator of nucleotide de novo synthesis, with potentially important implications for cancer etiology and drug resistance.
Insights
Transcription factor FOXK2 regulates nucleotide synthesis, promoting cancer growth and chemotherapy resistance. DNA damage represses FOXK2 SUMOylation, impacting drug resistance in hepatocellular carcinoma.
Area of Science:
- Molecular Biology
- Cancer Research
- Biochemistry
Background:
- Nucleotide de novo synthesis is crucial for cell proliferation.
- Dysregulation of this pathway is linked to cancer development and therapeutic resistance.
- Mechanisms underlying nucleotide synthesis dysregulation in cancer remain unclear.
Purpose of the Study:
- Identify regulatory mechanisms of nucleotide de novo synthesis in cancer.
- Investigate the role of transcription factor FOXK2 in this process.
- Determine the clinical significance of FOXK2 in hepatocellular carcinoma and drug resistance.
Main Methods:
- ChIP-Seq data analysis
- RNA sequencing (RNA-Seq)
- Luciferase-based promoter assays
- In vitro and in vivo biochemical and cell biology assays
Main Results:
- FOXK2 identified as a direct regulator of nucleotide de novo synthesis genes.
- FOXK2 promotes tumor growth and chemoresistance via SUMOylation-dependent nuclear translocation.
- DNA damage inhibits FOXK2 SUMOylation, impacting nucleotide synthesis and 5-FU resistance in hepatocellular carcinoma.
- Elevated FOXK2 expression correlates with poor prognosis in hepatocellular carcinoma patients.
Conclusions:
- FOXK2 is a novel regulator of nucleotide de novo synthesis.
- FOXK2 plays a significant role in cancer etiology and drug resistance.
- Targeting FOXK2 may offer new therapeutic strategies for cancer treatment.
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