SCD1 and SCD5 Modulate PARP-Dependent DNA Repair via Fatty Acid Desaturation in Glioblastoma

Area of Science:

• Biochemistry
• Cancer Biology
• Neuro-oncology

Background:

• Glioblastoma (GBM) exhibits aggressive growth dependent on fatty acid metabolism.
• Stearoyl-CoA desaturase-1 (SCD1) is implicated in GBM, but its brain-enriched isoform, SCD5, remains uncharacterized.

Purpose of the Study:

• To investigate the role of SCD5 in glioblastoma stem cell (GSC) maintenance, genomic stability, and therapeutic vulnerability.
• To elucidate the non-redundant functions of SCD1 and SCD5 in fatty acid metabolism and their impact on GSCs.

Main Methods:

• Shotgun lipidomics
• ¹³C metabolic flux analysis
• Functional genomics (genetic silencing)
• Orthotopic glioblastoma models
• Assessment of DNA damage repair and cell cycle progression

Main Results:

• SCD5 is essential for GSC maintenance and genomic stability, with higher expression in GSCs than differentiated cells.
• SCD1 and SCD5 have distinct roles in fatty acid desaturation, with SCD5 impacting C18:0 desaturation and sphingolipid remodeling.
• Silencing SCD1 or SCD5 impairs cell cycle, DNA repair, and GSC viability; SCD5 knockdown improves survival in GBM models.
• Loss of SCD activity leads to PARP1 hyperactivation, RAD51 depletion, compromised homologous recombination, and parthanatos.

Conclusions:

• SCD5 is a critical regulator of GSC function and genome integrity, representing a novel therapeutic target.
• Targeting SCD5 exploits a lipid-mediated vulnerability in GBM, potentially overcoming therapy resistance.
• Inhibition of SCD5 may enhance the efficacy of genotoxic and immunotherapeutic treatments for glioblastoma.