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PRPF19 Inhibition Attenuates Non-Small Cell Lung Cancer Progression through Impairing Citron Kinase-controlled Cytokinesis and Enhancing Anti-tumor Immune Responses [Prpf19_KP-1_RNAseq]

ABSTRACT: Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related death, primarily due to limited therapeutic targets and the emergence of drug resistance. In this study, we conducted CRISPR knockout screens to identify the pre-mRNA processing factor 19 (PRPF19) as a potential therapeutic target for NSCLC. Our findings revealed that PRPF19 is highly expressed in NSCLC, and its expression is negatively correlated with the clinical outcomes. Through functional validation, we confirmed that genetic ablation of PRPF19 significantly attenuated cancer progression both in vitro and in vivo. Mechanistically, we discovered that PRPF19 plays a crucial role in regulating the precise location of Citron Kinase (CIT) within the contractile ring, thereby sustaining the normal cytokinesis processes. Inhibition of PRPF19 resulted in cytokinesis failure, leading to micronuclei formation and activating the anti-tumor immune response through the TBK1-IFNs pathway. Taken together, our results demonstrate the critical involvement of the PRPF19-CIT axis in NSCLC progression and suggest that targeting PRPF19 represents a promising therapeutic approach for NSCLC patients.

ORGANISM(S): Musculus

PROVIDER: GSE259345 | GEO | 2024/03/03

REPOSITORIES: GEO

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PRPF19 Inhibition Attenuates Non-Small Cell Lung Cancer Progression through Impairing Citron Kinase-controlled Cytokinesis and Enhancing Anti-tumor Immune Responses [PRPF19_H2009_RNAseq]

Project description:Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related death, primarily due to limited therapeutic targets and the emergence of drug resistance. In this study, we conducted CRISPR knockout screens to identify the pre-mRNA processing factor 19 (PRPF19) as a potential therapeutic target for NSCLC. Our findings revealed that PRPF19 is highly expressed in NSCLC, and its expression is negatively correlated with the clinical outcomes. Through functional validation, we confirmed that genetic ablation of PRPF19 significantly attenuated cancer progression both in vitro and in vivo. Mechanistically, we discovered that PRPF19 plays a crucial role in regulating the precise location of Citron Kinase (CIT) within the contractile ring, thereby sustaining the normal cytokinesis processes. Inhibition of PRPF19 resulted in cytokinesis failure, leading to micronuclei formation and activating the anti-tumor immune response through the TBK1-IFNs pathway. Taken together, our results demonstrate the critical involvement of the PRPF19-CIT axis in NSCLC progression and suggest that targeting PRPF19 represents a promising therapeutic approach for NSCLC patients.

2024-03-03 | GSE259344 | GEO

PRPF19 Inhibition Attenuates Non-Small Cell Lung Cancer Progression through Impairing Citron Kinase-controlled Cytokinesis and Enhancing Anti-tumor Immune Responses [PRPF19_H2009_RNAseq]

Project description:PRPF19 Inhibition Attenuates Non-Small Cell Lung Cancer Progression through Impairing Citron Kinase-controlled Cytokinesis and Enhancing Anti-tumor Immune Responses [PRPF19_H2009_RNAseq]

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PRPF19 Inhibition Attenuates Non-Small Cell Lung Cancer Progression through Impairing Citron Kinase-controlled Cytokinesis and Enhancing Anti-tumor Immune Responses [Prpf19_KP-1_RNAseq]

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Project description:High expression of citron kinase contributes to the development of esophageal squamous cell carcinoma This study aimed to investigate the role and potential regulatory mechanism of citron kinase (CIT) in esophageal squamous cell carcinoma (ESCC).

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Project description:Protein regulator of cytokinesis 1 (PRC1) is a microtubule-bundling protein with essential roles in mitosis and cytokinesis. In this study we investigated the potential nuclear functions of PRC1 and the consequences of overexpression of PRC1 by using lung cancer cell lines stably expressing inducible expression constructs for PRC1. Ectopically expressed PRC1 resulted in proliferation defects, multi-nucleation and enlargement of cells which were directly linked to microtubule-bundling within the cytoplasm. Genome wide expression profiling by RNA sequencing revealed that the p53 pathway is activated upon overexpression of PRC1 resulting in cellular senescence. A mutant of PRC1 unable to enter into the nucleus induced the same gene sets as wildtype PRC1, suggesting that PRC1 has no nuclear-specific functions in lung cancer cells. The depletion of p53 switched the response to PRC1 overexpression or depletion from senescence to apoptosis. In addition, treatment with cisplatin, a commonly used chemotherapeutic drug, enhanced the proliferation defects due to deregulated PRC1, implicating PRC1 as a possible therapeutic target for cancer. Taken together, PRC1 needs to be tightly regulated to allow unperturbed proliferation of lung cancer cells.

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Project description:During cytokinesis in the budding yeast Saccharomyces cerevisiae, contraction of the cytokinetic ring and primary septum synthesis by chitin synthase II (Chs2p) are coupled processes. Myosin II (Myo1p), is involved in the actomyosin ring formation, required for proper cytokinesis, while Chs2p is responsible for the chitin primary septum formation which is necessary to stabilize the cytokinetic ring during its contraction. Morphological phenotypes of myo1∆ and chs2∆ mutants are therefore similar particularly in that both are unable to complete normal cytokinesis. A comparison between the global mRNA transcription profiles of myo1∆ and chs2∆ strains was conducted using oligonucleotide microarrays to establish if these cytokinesis mutants exhibited similar mRNA expression patterns and signature profiles were later generated from gene set enrichment analysis (GSEA). Genetic experiments were conducted to further test predictions based on the GSEA results. As reported previously in myo1∆ strains, a significant number of protein biosynthesis and RNA processing genes that may be attributed to regulation by cell integrity pathway(s) were also down-regulated in the chs2∆ strain. Genes coding for proteins involved in autophagy were coordinately upregulated only in the chs2∆ strain yet an ATG9 genetic knockout that completely blocks autophagy was viable in chs2∆ and myo1∆ genetic backgrounds.. However, the chs2∆ strain was significantly more susceptible to lysis by B-1,3-glucanase than myo1∆ and fks1 control strains. We interpret this result to indicate that these two cytokinesis mutant strains possess different cell wall properties. This interpretation was further supported by the observation that Slt2p hyperphosphorylation was detected in the chs2∆ strain yet expression of SLT2 was not required for cell viability. We conclude that in contrast to myo1∆ strains, chs2∆ strains do not activate the cell integrity pathway.

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Comparative phosphoproteomic analysis reveals signaling networks regulating monopolar and bipolar cytokinesis

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