NF-κB Is a Potential Therapeutic Target for Histone Deacetylase Inhibitor-Resistant Cutaneous T-Cell Lymphoma

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• Histone deacetylase inhibitors (HDACi), like vorinostat, are promising for T-cell lymphomas.
• Acquired resistance to HDACi limits their therapeutic efficacy, leading to disease relapse.

Purpose of the Study:

• To investigate the mechanisms of HDAC inhibitor resistance in cutaneous T-cell lymphoma (CTCL).
• To identify potential therapeutic strategies to overcome this resistance.

Main Methods:

• Established vorinostat-resistant CTCL cell lines through prolonged drug exposure.
• Utilized microarray analysis and in silico approaches to profile gene expression.
• Performed enrichment analyses using ChIP-Atlas and Enrichr.

Main Results:

• Identified 83 upregulated genes in resistant CTCL cells, with RELA/p65 showing the highest regulatory score.
• Demonstrated increased NF-κB pathway activation, marked by p65 upregulation and nuclear enrichment.
• Found that resistance involves acetylation-mediated inhibition of p65 ubiquitination, leading to protein stabilization.

Conclusions:

• Aberrant NF-κB activation is a key driver of HDAC inhibitor resistance in CTCL.
• Targeting the NF-κB pathway with agents like bortezomib or dimethyl fumarate can overcome resistance.
• NF-κB inhibition presents a viable strategy to enhance HDACi efficacy and improve outcomes for CTCL patients.