약제내성 삼중음성 유방암의 새로운 치료 표적으로서 RNA 결합 단백질 NONO의 기전에 대한 고찰

Abstract

Breast cancer (BC) is among the most prevalent types of cancer affecting women. The estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2) are important therapeutic targets in BC. However, triple-negative breast cancer (TNBC) has limited treatment options and no specific molecular targets, leading to poor clinical outcomes. Furthermore, TNBC is characterized by treatment failure owing to its aggressive nature, lymph node metastasis, and relatively high recurrence rate. This necessitates the identification of potential targets to enhance the therapeutic effect of TNBC treatment. RNA-binding proteins (RBPs) control messenger ribonucleic acid (mRNA) stability, splicing, translation efficiency, and the cellular distribution of proteins, thus significantly contributing to the regulation of various cellular functions. The human genome project (HGP) has identified more than 1500 structurally and functionally diverse RBPs. RBPs have recently demonstrated significant involvement in various human cancers, including BC, by influencing multiple oncogenic characteristics. This implies that RBPs are potential molecular targets for BC treatment. Genomic data were used in the present study to identify RBPs that exhibit specific expression patterns in TNBC. Consequently, RBP NONO, which contains a non-POU domain, was found to exhibit high expression levels in TNBC and to be correlated with unfavorable patient outcomes. The gene expression profile of NONO-depleted cells showed associations with cellular growth and proliferation, cell cycle regulation and cellular movement, and cell death and survival in TNBC cell lines. Surprisingly, the study findings indicate that NONO binds to and enhances the mRNA expression of the signal transducer and activator of transcription 3 (STAT3) in TNBC. Additionally, NONO directly binds to the STAT3 protein, resulting in enhanced preservation of its oncogenic function. We comprehensively screened a specific food and drug administration-approved candidate drug targeting NONO. The screening results demonstrated that auranofin effectively suppresses cell growth in TNBC, making it a potential NONO inhibitor. This implies that NONO serves as an upstream regulator of STAT3 at both the RNA and protein levels, thus influencing the growth and resistance mechanisms in these cancer cells. Overall, NONO exhibited great potential as a therapeutic target for the treatment of TNBC.