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C-terminal binding protein 2 in macrophage inflammation [RNA-seq]

ABSTRACT: Acute inflammation is critical for survival, but chronic immune mediated inflammation is a leading cause for disease and mortality worldwide , while our understanding of the pathogenesis and precise treatments are still limited. Here we investigate the role of the transcriptional corepressors CTBP 1 and 2 in murine and human macrophage inflammation using loss of function models to show that CTBP2 but not CTBP1 controls inflammatory gene expression . We find that CTBP2 binds to cis-regulatory elements of inflammatory genes together with the transcription factors NFκB and AP-1 and forms a corepressor complex. Rescue of Ctbp1/2 double knockout cells with full length CTBP2 potently represses inflammatory responses while a monomeric mutant does not. Differential profiling of CTBP2’s wild type and monomeric interactome confirms oligomer-specific interactions with multiple repressors including the NuRD complex, WIZ and KDM1A. Conversely, monomers retain their ability to interact with inflammatory transcription factors and polymerase 2, boosting transcription of inflammatory genes. Our findings point to an important function for CTBP2 in the resolution of inflammation, which may contribute to the progression of inflammatory disorders and which may offer therapeutic targets in the future.

ORGANISM(S): Mus musculus

PROVIDER: GSE287789 | GEO | 2025/06/03

REPOSITORIES: GEO

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Project description:Pancreatic ductal adenocarcinoma (PDAC) remains among the most lethal of human cancers underscoring the need to identify new therapeutic vulnerabilities. Previously, we reported high expression of transcriptional co-regulators C-terminal binding proteins (CtBP) 1 and 2 in human PDAC, however their precise role in PDAC formation or progression remains unclear. Here, we have studied PDAC tumor dependency on CtBPs for growth and metastasis using an orthotopic syngeneic pancreatic tumor mouse model. CRISPR-based homozygous deletion of Ctbp2 dramatically decreased PDAC tumor growth, drastically reduced metastatic potential, and significantly prolonged survival. Interrogating differential gene expression of the orthotopic PDAC tumors from CtBP2 WT vs. CtBP2 KO cohorts, we identified significant downregulation of the EGFR-superfamily receptor ErbB3 in CtBP2 KO tumors, and further determined that CtBP regulates expression of both the ErbB2 and 3 EGFR superfamily genes in PDAC cells. We therefore hypothesized that CtBP regulation of physiologic ErbB2/3 signaling contributes, in part, to PDAC growth and metastasis. Indeed, we observed that CtBP2 KO cells exhibited severely attenuated activation of phospho-Akt after neuregulin stimulation of ErbB2/3, and we demonstrate that human PDAC cells also show CtBP dependence of ErbB2/3 expression. Our results suggest that a subset of PDAC tumors is dependent on physiologic ErbB2/3 signaling and could be targeted by pharmacologic inhibitors of ErbB2 and/or ErbB3. Providing proof of concept, the ErbB2-targeted multikinase inhibitor lapatinib, but not the ErbB1/EGFR targeted agent erlotinib, effectively killed ErbB3 expressing PDAC cells, while CtBP2 KO cells where ErbB3 expression was extinguished, were resistant to lapatinib. Taken together, our data suggests that ErBb2/3 targeted therapeutics can effectively target a critical PDAC dependency on physiologic ErbB2/3 signaling which is the result of CtBP’s oncogenic transcriptional program that drives PDAC tumor progression.

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C-terminal binding protein 2 in macrophage inflammation [RNA-seq]

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