Targeting SRSF6 to Enhance Cisplatin Sensitivity by Modulating Redox Balance via NFE2L1 exon 4 Splicing in ESCC

Area of Science:

• Oncology
• Molecular Biology
• Cellular Biology

Background:

• Cancer cells' survival mechanisms under oxidative stress are not fully understood.
• Redox homeostasis is critical for cancer cell adaptation and proliferation.
• Esophageal squamous cell carcinoma (ESCC) exhibits increased oxidative stress.

Purpose of the Study:

• To investigate the role of serine/arginine-rich splicing factor 6 (SRSF6) in ESCC redox homeostasis.
• To elucidate the molecular mechanisms underlying SRSF6-mediated regulation of NFE2L1 splicing.
• To evaluate the therapeutic potential of targeting the SRSF6-NFE2L1 axis in ESCC.

Main Methods:

• Analysis of oxidative stress markers in ESCC.
• Investigating SRSF6 binding to NFE2L1 exon 4 using splicing assays.
• Utilizing antisense oligonucleotides (ASOs) to inhibit SRSF6.
• Assessing apoptosis and ferroptosis induction.
• Evaluating cisplatin (CDDP) sensitivity in combination with SRSF6 inhibition.

Main Results:

• SRSF6 maintains redox homeostasis by promoting specific NFE2L1 isoforms that enhance antioxidant capacity.
• SRSF6 inhibition leads to increased NFE2L1-S isoform, elevated ROS, and induced apoptosis/ferroptosis.
• A positive feedback loop exists between SRSF6 and NFE2L1.
• SRSF6 ASOs significantly suppressed ESCC cell growth.
• Inhibition of the SRSF6-NFE2L1 axis enhanced CDDP sensitivity and therapeutic efficacy.

Conclusions:

• The SRSF6-NFE2L1 axis is crucial for ESCC redox homeostasis and tumor progression.
• SRSF6 is a potential therapeutic target for improving ESCC treatment outcomes.
• Targeting this axis can overcome chemoresistance and enhance the efficacy of existing therapies like CDDP.