Phosphorylation of POU3F3 Mediated Nuclear Translocation Promotes Proliferation in Non-Small Cell Lung Cancer through Accelerating ATP5PF Transcription and ATP Production.

Summary

In RAS-mutant NSCLC cells, ERK1 phosphorylates POU3F3 at S393, enabling importin-β1–mediated nuclear translocation. Nuclear POU3F3 binds the ATP5PF promoter, upregulates ATP5PF and ATP production, and enhances proliferation and migration, defining a RAS–POU3F3–ATP5PF axis that drives tumor progression.

Key Findings

• POU3F3 undergoes ERK1-dependent S393 phosphorylation and importin-β1–mediated nuclear translocation in RAS-mutant NSCLC cells.
• Nuclear POU3F3 binds the ATP5PF promoter, increasing ATP5PF transcription and cellular ATP production.
• Enhanced ATP5PF/ATP augments NSCLC proliferation and migration; defining a RAS–POU3F3–ATP5PF axis.
• RNA-seq and ChIP assays mechanistically supported transcriptional regulation by POU3F3.

Clinical Implications

Therapeutic strategies could target ERK1–POU3F3 signaling, nuclear import, or ATP5PF to disrupt OXPHOS reliance in RAS-mutant NSCLC; it also supports combining OXPHOS inhibitors with RAS/ERK pathway blockade.

Limitations

• Preclinical cell-line based evidence without in vivo efficacy data in the abstract
• Generalizability to non–RAS-mutant contexts and interpatient heterogeneity remains to be tested

Future Directions

Validate the axis in vivo, assess druggability (e.g., ERK1–POU3F3 interaction, import pathways, ATP5PF), and test combinations of OXPHOS and RAS/ERK inhibitors in RAS-mutant NSCLC models.