Loss of RBM45 inhibits breast cancer progression by reducing the SUMOylation of IRF7 to promote IFNB1 transcription
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1022472 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR26225346_1.fastq.gz | Fastqsanger.gz | |||
| SRR26225346_2.fastq.gz | Fastqsanger.gz | |||
| SRR26225348_1.fastq.gz | Fastqsanger.gz | |||
| SRR26225348_2.fastq.gz | Fastqsanger.gz |
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Project description: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-β 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.
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Project description:Despite the pleiotropic role of SUMOylation, this pathway mainly functions to repress innate immunity in myeloid cells. Inactivating SUMOylation triggers a potent basal type I interferon (IFN1) response, amplified and coupled with an inflammatory response upon stimulation. These findings transposed to pre-clinical models with the demonstration that SUMOylation inhibitors (SUMOi) activate antitumor immunity in an IFN1-dependent manner. Yet, how SUMOylation represses immune signaling remains largely unknown. We identified murine MORC3, a critical transcriptional repressor of the IFNB1 gene, as the top SUMO2/3 substrate in myeloid cells. We show that, in human monocytes, SUMO functions to repress basal IFNB1 in cis through an atypical/repeated MORC3-regulated element (MRE) concentrating/homing multiple PU.1 binding motifs. Inhibiting SUMOylation induces a 3D genome reorganization centered on the MRE, which, in turn, acquires both insulator and PU.1-driven enhancer activities, together with loss of H3.3 and H3K9me3 repressive marks and increased PU-1 binding. Paradoxically, MORC3, that binds PU.1, is massively recruited, yet unable to repress the MRE. Finally, we show that both MORC3 ATPase cycle and SUMOylation are critical for full MORC3 repressive activity. Our study identifies an unconventional mechanism in which SUMO, in concert with MORC3, orchestrates a metastable H3.3/H3K9me3 heterochromatin state on a multi-PU.1 binding platform element to shutdown unscheduled myeloid-specific IFN1 response.
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