KDM1A inhibition increases UVA toxicity and enhances photodynamic therapy efficacy
Shaila Mudambi1,2, Megan Fitzgerald1,2, Paula Pera1,2
1Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA.
Background:
Lysine-specific histone demethylase 1 (KDM1A/LSD1) regulates multiple cellular functions, including cellular proliferation, differentiation, and DNA repair. KDM1A is overexpressed in squamous cell carcinoma of the skin and inhibition of KDM1A can suppress cutaneous carcinogenesis. Despite the role of KDM1A in skin and DNA repair, the effect of KDM1A inhibition on cellular ultraviolet (UV) response has not been studied.
Methods:
The ability of KDM1A inhibitor bizine to modify cell death after UVA and UVB exposure was tested in normal human keratinocytes and melanocytes, HaCaT, and FaDu cell lines. KDM1A was also downregulated using shRNA and inhibited by phenelzine in HaCaT and FaDu cells to confirm the role of KDM1A in UVA response. In addition, cellular reactive oxygen species (ROS) changes were assessed by a lipid-soluble fluorescent indicator of lipid oxidation, and ROS-related gene regulation using qPCR. During photodynamic therapy (PDT) studies HaCaT and FaDu cells were treated with aminolaevulinic acid (5-ALA) or HPPH (2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a) sodium and irradiated with 0-8 J/cm2 red LED light.
Results:
KDM1A inhibition sensitized cells to UVA radiation-induced cell death but not to UVB. KDM1A inhibition increased ROS generation as detected by increased lipid peroxidation and the upregulation of ROS-responsive genes. The effectiveness of both ALA and HPPH PDT significantly improved in vitro in HaCaT and FaDu cells after KDM1A inhibition.
Conclusion:
KDM1A is a regulator of cellular UV response and KDM1A inhibition can improve PDT efficacy.
Insights
Inhibiting KDM1A (lysine-specific histone demethylase 1) enhances cellular sensitivity to UVA radiation and boosts photodynamic therapy effectiveness. This study reveals KDM1A’s role in UV response.
Area of Science:
- Molecular Biology
- Dermatology
- Oncology
Background:
- Lysine-specific histone demethylase 1 (KDM1A/LSD1) is crucial for cellular functions like proliferation, differentiation, and DNA repair.
- KDM1A overexpression is linked to skin squamous cell carcinoma, and its inhibition can suppress skin cancer.
- The impact of KDM1A inhibition on cellular response to ultraviolet (UV) radiation remained uninvestigated.
Purpose of the Study:
- To investigate the role of KDM1A in cellular response to UVA and UVB radiation.
- To determine if KDM1A inhibition affects UV-induced cell death and reactive oxygen species (ROS) generation.
- To evaluate the potential of KDM1A inhibition in enhancing photodynamic therapy (PDT) efficacy.
Main Methods:
- KDM1A was inhibited using bizine, shRNA, and phenelzine in various human cell lines (keratinocytes, melanocytes, HaCaT, FaDu).
- Cell death following UVA/UVB exposure was assessed.
- Cellular ROS levels were measured using lipid peroxidation indicators and qPCR for ROS-related genes.
- PDT efficacy was tested using aminolaevulinic acid (5-ALA) or HPPH with red LED light irradiation.
Main Results:
- KDM1A inhibition sensitized cells to UVA-induced death, but not UVB.
- Inhibition led to increased ROS generation and upregulation of ROS-responsive genes.
- KDM1A inhibition significantly improved the in vitro efficacy of both 5-ALA and HPPH PDT.
Conclusions:
- KDM1A acts as a regulator of the cellular response to UV radiation.
- Inhibiting KDM1A enhances cellular sensitivity to UVA and improves PDT effectiveness.
- Targeting KDM1A presents a potential strategy for improving UV-related cancer therapies.
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