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Snail enhances arginine synthesis by inhibiting ubiquitination-mediated degradation of ASS1

ABSTRACT: Snail is a dedicated transcriptional repressor and acts as a master inducer of EMT and metastasis, yet the underlying signaling cascades triggered by Snail still remain elusive. Here we report that Snail promotes colorectal cancer (CRC) migration by preventing non-coding RNA LOC113230-mediated degradation of arginosuccinate synthase 1 (ASS1). LOC113230 is a novel Snail target gene, and Snail binds to the functional E-boxes within its proximal promoter to repress its expression in response to TGF-? induction. Ectopic expression of LOC113230 potently suppresses CRC cell growth, migration and lung metastasis in xenograft experiments. Mechanistically, LOC113230 acts as a scaffold to facilitate recruiting LRPPRC and the TRAF2 E3 ubiquitin ligase to ASS1, resulting in enhanced ubiquitination and degradation of ASS1 and decreased arginine synthesis. Moreover, elevated ASS1 expression is essentail for CRC growth and migration. Collectively, these findings suggest that TGF-? and Snail promote arginine synthesis via inhibiting LOC113230 mediated LRPPRC/TRAF2/ASS1 complex assembly and this complex can serve as potential target for the development of new therapeutic approaches to treat CRC.

SUBMITTER: Prof. Hao Jia

PROVIDER: S-SCDT-EMBOR-2020-51780-T | biostudies-other |

REPOSITORIES: biostudies-other

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Snail enhances arginine synthesis by inhibiting ubiquitination-mediated degradation of ASS1.

Project description:Snail is a dedicated transcriptional repressor and acts as a master inducer of EMT and metastasis, yet the underlying signaling cascades triggered by Snail still remain elusive. Here, we report that Snail promotes colorectal cancer (CRC) migration by preventing non-coding RNA LOC113230-mediated degradation of argininosuccinate synthase 1 (ASS1). LOC113230 is a novel Snail target gene, and Snail binds to the functional E-boxes within its proximal promoter to repress its expression in response to TGF-β induction. Ectopic expression of LOC113230 potently suppresses CRC cell growth, migration, and lung metastasis in xenograft experiments. Mechanistically, LOC113230 acts as a scaffold to facilitate recruiting LRPPRC and the TRAF2 E3 ubiquitin ligase to ASS1, resulting in enhanced ubiquitination and degradation of ASS1 and decreased arginine synthesis. Moreover, elevated ASS1 expression is essential for CRC growth and migration. Collectively, these findings suggest that TGF-β and Snail promote arginine synthesis via inhibiting LOC113230-mediated LRPPRC/TRAF2/ASS1 complex assembly and this complex can serve as potential target for the development of new therapeutic approaches to treat CRC.

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TRIM59-mediated ferroptosis enhances neuroblastoma development and chemosensitivity through p53 ubiquitination and degradation

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Project description:Methyl-CpG-binding protein 2 (MeCP2) facilitates the carcinogenesis and progression of several types of cancer. However, its role in breast cancer and the relevant molecular mechanism remain largely unclear. In this study, analysis of the Cancer Genome Atlas (TCGA) data that MeCP2 expression was significantly upregulated in breast cancer tissues, and high MeCP2 expression was correlated with poor overall survival. Knockdown of MeCP2 inhibited breast cancer cell proliferation and G1-S cell cycle transition and migration as well as induced cell apoptosis in vitro. Moreover, MeCP2 knockdown suppressed cancer cell growth in vivo. Investigation of the molecular mechanism showed that MeCP2 repressed RPL11 and RPL5 transcription by binding to their promoter regions. TCGA data revealed significantly lower RPL11 and RPL5 expression in breast cancer tissues; additionally, overexpression of RPL11/RPL5 significantly suppressed breast cancer cell proliferation and G1-S cell cycle transition and induced apoptosis in vitro. Furthermore, RPL11 and RPL5 suppressed ubiquitination-mediated P53 degradation through direct binding to MDM2. This study demonstrates that MeCP2 promotes breast cancer cell proliferation and inhibits apoptosis through suppressing RPL11 and RPL5 transcription by binding to their promoter regions.

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DIRAS3 enhances RNF19B-mediated RAC1 ubiquitination and degradation in non-small-cell lung cancer cells.

Project description:Distant metastasis remains the leading cause of high mortality in patients with non-small-cell lung cancer (NSCLC). DIRAS3 is a candidate tumor suppressor protein that is decreased in various tumors. However, the regulatory mechanism of DIRAS3 on metastasis of NSCLC remains unclear. Here, we found that DIRAS3 suppressed the migration of NSCLC cells. Besides, DIRAS3 stimulated the polyubiquitination of RAC1 and suppressed its protein expression. Furthermore, RNF19B, a member of the RBR E3 ubiquitin ligase family, was observed to be the E3 ligase involved in the DIRAS3-induced polyubiquitination of RAC1. DIRAS3 could promote the binding of RAC1 and RNF19B, thus enhancing the degradation of RAC1 by the ubiquitin-proteasome pathway. Finally, the DIRAS3-RNF19B-RAC1 axis was confirmed to be associated with the malignant progression of NSCLC. These findings may be beneficial for developing potential prognostic markers of NSCLC and may provide an effective treatment strategy.

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Project description:Cell polarity is essential for ameloblast differentiation and enamel formation. Smurf1 can mediate cell polarization through ubiquitination degradation of specific substrates. But it remains unclear whether Smurf1 could regulate ameloblast polarity and the underlying mechanism. Here, immuno-fluorescence staining and RT-qPCR were applied to detect the expression of Smurf1 and F-actin. A mouse lower incisor defect model was constructed. Scanning electron microscope, rat lower incisor culture, western blot, wound healing assay and trans-well migration assay were performed to detect the influence of Smurf1 knockdown on ameloblast. IF double staining, western blot and co-immunoprecipitation were conducted to detect the interaction between Smurf1 and RhoA. The in vivo experiment was also performed. We found that Smurf1 was mainly expressed in the membrane and cell cortex of ameloblast, similar to F-actin. Smurf1 expression increased along ameloblast polarization and differentiation. After knocking down Smurf1, the cytoskeleton and cell morphology changed and the cell polarity was damaged. Smurf1 regulated ameloblast polarity through ubiquitination degradation of activated RhoA in vitro. Local knockdown of Smurf1 in rat lower incisor ameloblast resulted in ameloblast polarity loss, enamel matrix secretion disorder and chalky enamel, but RhoA inhibitor Y-27632 could reverse this effect. Collectively, Smurf1 could regulate the polarization of ameloblast through ubiquitination degradation of activated RhoA, which contributed to the knowledge of tooth development and provided new research ideas for cell polarity.

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Project description:This SuperSeries is composed of the SubSeries listed below.

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