Loss of RBM45 inhibits breast cancer progression by reducing the SUMOylation of IRF7 to promote IFNB1 transcription
Type I interferons exhibit anti-proliferative and anti-cancer activities, but their regulatory mechanisms in cancer have not been fully elucidated. RNA binding proteins are master orchestrators of gene expression regulation and are closely related to tumor progression. Here we show that the upregulated RNA binding protein RBM45 correlates with poor prognosis in breast cancer. Depletion of RBM45 suppresses breast cancer progression both in cultured cells and xenograft mouse models. Further analysis reveals that depletion of RBM45 inhibits breast cancer progression through regulating type I interferon signaling, in particular by elevating IFN-ß production. Mechanistically, RBM45 coordinates with TRIM28 to regulate IFNB1 transcription. We identify that RRM2 and RRM3 domains of RBM45 are required for TRIM28 binding. Moreover, RBM45 could directly interact with IRF7, whereas RBM45 without any RRM domain attenuates its ability to interact with IRF7. Importantly, RBM45 recruits TRIM28 to IRF7 and stimulates its SUMOylation, thereby repressing IFNB1 transcription. Loss of RBM45 reduced the SUMOylation of IRF7 by reducing the interaction between TRIM28 and IRF7 to promote IFNB1 transcription, leading to the inhibition of breast cancer progression. Taken together, our finding uncovers a key role of RBM45 in modulating type I interferon signaling and cancer aggressive progression, implicating RBM45 as a potential therapeutic target in breast cancer. Overall design: To investigate the effects of the knockdown  of RBM45 gene on breast cancer MCF7 cells, we established two RBM45 knockdown MCF7 cell lines and then performed RNA-seq sequencing analysis.