SUMOylation Protects FASN Against Proteasomal Degradation in Breast Cancer Cells Treated with Grape Leaf Extract

Area of Science:

• Biochemistry
• Oncology
• Phytochemistry

Background:

• Breast cancer therapies face challenges with recurrence and drug resistance.
• Antioxidant plant compounds, like flavonoids, show potential as antineoplastic agents with fewer side effects.
• Fatty-acid synthase (FASN) is crucial for fatty acid synthesis and a target in cancer therapy.

Purpose of the Study:

• To investigate the novel regulation of FASN by small ubiquitin-like modifier (SUMO)ylation in breast cancer.
• To evaluate the antitumorigenic effects of *Vitis vinifera* L. cv Vermentino leaf hydroalcoholic extract on FASN and breast cancer progression.
• To explore the role of FASN SUMOylation in protein stability and oncogenic activity.

Main Methods:

• Phenolic compound characterization using liquid chromatography-mass spectrometry (LC-MS).
• Assessment of FASN and UBC9 expression via Western blotting, co-immunoprecipitation (Co-IP), and RT-PCR.
• Evaluation of cell viability, clonogenicity, and cell cycle using MTT, clonogenicity assays, and FACS analysis.
• Investigation of FASN SUMOylation and protein stability through SUMO2 silencing.

Main Results:

• Vermentino extract significantly reduced FASN and UBC9 protein levels.
• FASN was found to be SUMOylated in human breast cancer tissues and cell lines.
• SUMOylation protects FASN from proteasomal degradation; its absence reduces FASN protein stability.
• Vermentino extract inhibited FASN SUMOylation and its associated oncogenic effects on lipid metabolism.

Conclusions:

• SUMOylation of FASN promotes its stability and contributes to oncogenesis via lipid metabolism alteration.
• Vermentino leaf extract demonstrates antitumorigenic effects by destabilizing FASN through inhibition of its SUMOylation.
• This study highlights a novel therapeutic mechanism for Vermentino extract in combating breast cancer, particularly drug-resistant forms.