Dual targeting of KDM1A and antioxidants is an effective anticancer strategy

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Lysine Specific Demethylase 1 (KDM1A/LSD1) regulates mitochondrial respiration and stabilizes hypoxia-inducible factor 1A (HIF-1A).
• HIF-1A influences reactive oxygen species (ROS) levels via glucose metabolism and antioxidant production.
• The specific role of KDM1A in cellular ROS response was previously undescribed.

Purpose of the Study:

• To investigate the role of KDM1A in regulating cellular ROS response.
• To evaluate the efficacy of KDM1A inhibitors in combination with ROS-inducing cancer therapies.
• To elucidate the mechanism by which KDM1A inhibition affects ROS sensitivity.

Main Methods:

• Utilized KDM1A inhibitors and antioxidant treatments (N-acetyl cysteine, buthionine sulfoximine, auranofin) in rhabdomyosarcoma cell lines (Rh28, Rh30).
• Assessed cellular ROS levels, mitochondrial respiration, and HIF-1A induction.
• Investigated the impact of HIF-1A overexpression and glutathione depletion.

Main Results:

• KDM1A inhibition sensitized cells to oxidative stress, increasing total cellular ROS.
• KDM1A inhibition reduced basal mitochondrial respiration and impaired HIF-1A induction following ROS exposure.
• HIF-1A overexpression rescued cells from KDM1A inhibition-induced ROS sensitivity, implicating HIF-1A and glutathione depletion in the observed effects.
• KDM1A inhibitor bizine synergized with antioxidant-depleting agents.

Conclusions:

• KDM1A plays a novel role in regulating HIF-1A function under oxidative stress.
• KDM1A inhibition enhances ROS sensitivity through HIF-1A and glutathione depletion.
• Dual targeting of KDM1A and antioxidant systems presents a promising combination anticancer strategy.