Transcriptome reprogramming through alternative splicing triggered by apigenin drives cell death in triple-negative breast cancer

Area of Science:

• * Oncology
• * Molecular Biology
• * Nutraceutical Research

Background:

• * Triple-negative breast cancer (TNBC) exhibits aggressive behavior and resistance due to transcriptome alterations.
• * Alternative splicing (AS) significantly contributes to cancer-specific transcriptomes, promoting TNBC growth and resistance.
• * Reprogramming AS circuitry is crucial for delaying tumorigenesis or enhancing therapy response in TNBC.

Purpose of the Study:

• * To investigate the effect of the flavonoid apigenin on TNBC-associated alternative splicing.
• * To determine if apigenin can reprogram the TNBC transcriptome-wide AS.
• * To assess apigenin's impact on tumor growth and apoptosis in vivo.

Main Methods:

• * Comparative transcriptomic analyses of human TNBC tumors and non-tumor tissues.
• * Investigation of apigenin's association with splicing factors, specifically heterogeneous nuclear ribonucleoprotein A2 (hnRNPA2).
• * In vivo studies using TNBC xenograft mouse models to evaluate apigenin's effects on proliferation and apoptosis.

Main Results:

• * Apigenin was shown to reprogram TNBC-associated AS transcriptome-wide, with affected events enriched in hnRNPA2 substrates.
• * Apigenin shifted cancer-associated alternative spliced isoforms (ASI) towards those found in non-tumor tissues.
• * Apigenin preferentially affected splicing of anti-apoptotic and proliferation factors, reduced tumor proliferation, and increased apoptosis in vivo, halting TNBC growth.

Conclusions:

• * Apigenin effectively reprograms transcriptome-wide TNBC-specific AS, inducing apoptosis and hindering tumor growth.
• * These findings highlight the significant impact of nutraceuticals like apigenin in altering cancer transcriptomes.
• * Apigenin presents a potential therapeutic strategy for influencing outcomes in triple-negative breast cancer treatment.