DDRGK1 Enhances Osteosarcoma Chemoresistance via Inhibiting KEAP1-Mediated NRF2 Ubiquitination

Area of Science:

• Molecular Oncology
• Cancer Therapeutics
• Biochemistry

Background:

• Chemoresistance presents a significant challenge in osteosarcoma (OS) treatment, with underlying mechanisms requiring elucidation.
• DDRGK domain-containing protein 1 (DDRGK1) has emerged as a potential key player in OS chemoresistance.

Purpose of the Study:

• To investigate the role of DDRGK1 in osteosarcoma chemoresistance.
• To elucidate the molecular mechanisms by which DDRGK1 influences chemoresistance.
• To evaluate DDRGK1 as a potential therapeutic target for improving osteosarcoma treatment.

Main Methods:

• Bioinformatic and tissue analyses to correlate DDRGK1 expression with OS stage and prognosis.
• Quantitative proteomic analysis to identify DDRGK1's role in mitochondrial oxidative phosphorylation.
• DDRGK1 knockout experiments to assess effects on reactive oxygen species (ROS), NRF2 stability, and chemosensitivity.
• In vivo studies using mouse models to validate therapeutic potential.

Main Results:

• Higher DDRGK1 expression correlates with advanced OS stage and poor prognosis.
• DDRGK1 is critical for mitochondrial oxidative phosphorylation and NRF2 stability.
• DDRGK1 knockout leads to ROS accumulation and enhanced chemosensitivity to doxorubicin (DOX) and etoposide by destabilizing NRF2.
• DDRGK1 knockout significantly improves in vivo chemosensitivity to DOX in osteosarcoma.

Conclusions:

• DDRGK1 promotes osteosarcoma chemoresistance by inhibiting NRF2 degradation.
• Targeting DDRGK1 or its pathway offers a promising strategy to overcome chemoresistance in osteosarcoma.
• Combining DDRGK1 knockdown with DOX presents a potential novel therapeutic approach for OS.