FBXW7 modulates cellular stress response and metastatic potential through ​HSF1 post-translational modification

Area of Science:

• Cellular Biology
• Molecular Oncology
• Stress Response Mechanisms

Background:

• Heat-shock factor 1 (HSF1) is crucial for eukaryotic cellular adaptation to stress.
• The HSF1 pathway is dysregulated in cancer, promoting malignancy.
• Mechanisms controlling HSF1 activity and cellular stress response remain incompletely understood.

Purpose of the Study:

• To elucidate the regulatory mechanisms of HSF1.
• To investigate the role of FBXW7α in HSF1 regulation.
• To determine the implications of HSF1 dysregulation in melanoma progression.

Main Methods:

• Investigated the interaction between FBXW7α and HSF1 using biochemical assays.
• Analyzed the effect of FBXW7α on HSF1 ubiquitination and degradation.
• Assessed HSF1 nuclear localization and transcriptional activity in melanoma cells with varying FBXW7α levels.

Main Results:

• Identified a conserved motif in HSF1 phosphorylated by GSK3β and ERK1, mediating FBXW7α interaction.
• Demonstrated that FBXW7α ubiquitinates HSF1, promoting its degradation.
• Observed impaired HSF1 degradation and defective stress response attenuation upon FBXW7α loss.
• Found FBXW7α mutations or downregulation in melanoma, correlating with HSF1 nuclear stabilization, increased metastasis, and disease progression.

Conclusions:

• FBXW7α acts as a key regulator of HSF1 stability through ubiquitination.
• FBXW7α deficiency leads to HSF1 accumulation, activating pro-invasion transcriptional programs in melanoma.
• This identifies a critical post-translational regulatory mechanism of HSF1 in both stress adaptation and cancer metastasis.