2. Academic Validation
  3. FOXK2 affects cancer cell response to chemotherapy by promoting nucleotide de novo synthesis

FOXK2 affects cancer cell response to chemotherapy by promoting nucleotide de novo synthesis

  • Drug Resist Updat. 2023 Mar:67:100926. doi: 10.1016/j.drup.2023.100926.
Yingge Li 1,  Jie Chen 2,  Bin Wang 3,  Ziwen Xu 4,  Ci Wu 4,  Junfeng Ma 4,  Qibin Song 2,  Qing Geng 5,  Jinming Yu 6,  Huadong Pei 7,  Yi Yao 8
Affiliations

Affiliations

  • 1 Cancer Center, Renmin Hospital of Wuhan University, Wuhan 430060, China; Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC 20057, USA.
  • 2 Cancer Center, Renmin Hospital of Wuhan University, Wuhan 430060, China.
  • 3 Department of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, China.
  • 4 Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC 20057, USA.
  • 5 Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, China.
  • 6 Cancer Center, Renmin Hospital of Wuhan University, Wuhan 430060, China; Department of Radiation Oncology, Shandong University Cancer Center, Jinan, Shandong 250117, China. Electronic address: [email protected].
  • 7 Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC 20057, USA. Electronic address: [email protected].
  • 8 Cancer Center, Renmin Hospital of Wuhan University, Wuhan 430060, China. Electronic address: [email protected].
PMID: 36682222 DOI: 10.1016/j.drup.2023.100926
Abstract

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.

Keywords

Chemotherapy resistance; DNA damage response; FOXK2; Nucleotide de novo synthesis; SUMOylation.

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