miR-432 Induces NRF2 Stabilization by Directly Targeting KEAP1

Area of Science:

• Molecular biology
• Cancer research
• Gene regulation

Background:

• NF-E2-related factor 2 (NRF2) is a key regulator of cellular stress responses, typically inhibited by Kelch-like ECH-associated protein 1 (KEAP1).
• Aberrant NRF2 stabilization in cancer promotes tumor growth and chemoresistance.
• MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression, but their role in the NRF2-KEAP1 pathway is not well understood.

Purpose of the Study:

• To investigate the role of microRNA-432-3p (miR-432-3p) in regulating the NRF2-KEAP1 pathway.
• To determine the impact of miR-432-3p on chemoresistance in esophageal squamous cell carcinoma (ESCC).

Main Methods:

• Investigated the direct binding of miR-432-3p to KEAP1 mRNA.
• Assessed the effect of miR-432-3p overexpression and inhibition (using CRISPR/Cas9) on NRF2 activity and chemoresistance in ESCC cells treated with cisplatin (CDDP).
• Analyzed miR-432-3p and KEAP1 expression levels in primary ESCC tumors.

Main Results:

• miR-432-3p directly binds to KEAP1 mRNA, leading to its downregulation and subsequent NRF2 activation.
• Overexpression of miR-432-3p decreased ESCC cell sensitivity to cisplatin, while its inhibition increased sensitivity.
• miR-432-3p was found to be overexpressed in a majority of ESCC tumors, with an inverse correlation to KEAP1 expression.

Conclusions:

• miR-432-3p positively regulates NRF2 activity by targeting KEAP1.
• This miRNA-mediated regulation contributes to chemoresistance in esophageal squamous cell carcinoma.
• The findings elucidate a novel mechanism of NRF2 stabilization in cancer and suggest miR-432-3p as a potential therapeutic target.