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Tiam1 methylation by NSD2 promotes Rac1 signaling activation and cancer metastasis II

ABSTRACT: Metastasis is the key cause of failure of cancer therapy or mortality, but targeting metastatic seeding and colonization remains an unresolved challenge. Here, we report a novel molecular event in cancer metastasis mediated by NSD2/Rac1 signaling and provide a detailed mechanistic investigation of cancer metastasis. We found that NSD2, a histone methyltransferase responsible for di-methylating histone 3 at lysine 36, was overexpressed in metastatic tumors, and overexpressed NSD2 enhanced tumor metastasis both in vitro and in vivo. We further investigated that NSD2 promoted tumor metastasis by activating the Rac1 signaling pathway. Mechanistically, NSD2 methylated Tiam1, a guanine nucleotide exchange factor that facilitates GDP-Rac1 to GTP-Rac1 transition at K724. We demonstrated that Tiam1 K724 methylation plays a crucial role in Tiam1 activation and GDP-Rac1 to GTP-Rac1 transition. Specifically, we identified that Tiam1 K724 methylation could be a predictive factor in cancer prognosis, and we demonstrated that pharmacological blocking of Tiam1 K724 methylation by employing a transmembrane peptide inhibited tumor metastasis both in vitro and in vivo. Thus, NSD2-methylated Tiam1 promoted Rac1 signaling activation and cancer metastasis, which might provide novel insights into tumor metastasis inhibition.

ORGANISM(S): Homo sapiens

PROVIDER: GSE237996 | GEO | 2023/07/29

REPOSITORIES: GEO

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Tiam1 methylation by NSD2 promotes Rac1 signaling activation and cancer metastasis

Project description:Metastasis is the key cause of failure of cancer therapy or mortality, but targeting metastatic seeding and colonization remains an unresolved challenge. Here, we report a novel molecular event in cancer metastasis mediated by NSD2/Rac1 signaling and provide a detailed mechanistic investigation of cancer metastasis. We found that NSD2, a histone methyltransferase responsible for di-methylating histone 3 at lysine 36, was overexpressed in metastatic tumors, and overexpressed NSD2 enhanced tumor metastasis both in vitro and in vivo. We further investigated that NSD2 promoted tumor metastasis by activating the Rac1 signaling pathway. Mechanistically, NSD2 methylated Tiam1, a guanine nucleotide exchange factor that facilitates GDP-Rac1 to GTP-Rac1 transition at K724. We demonstrated that Tiam1 K724 methylation plays a crucial role in Tiam1 activation and GDP-Rac1 to GTP-Rac1 transition. Specifically, we identified that Tiam1 K724 methylation could be a predictive factor in cancer prognosis, and we demonstrated that pharmacological blocking of Tiam1 K724 methylation by employing a transmembrane peptide inhibited tumor metastasis both in vitro and in vivo. Thus, NSD2-methylated Tiam1 promoted Rac1 signaling activation and cancer metastasis, which might provide novel insights into tumor metastasis inhibition.

2023-07-23 | GSE237714 | GEO

Investigating TIAM1 in NSCLC (ChIP-Seq)

Project description:The T lymphoma invasion and metastasis inducing protein 1 (TIAM1) is a guanine nucleotide exchange factor (GEF) that activates the small GTPase RAC1. We have shown that nuclear TIAM1 promotes the migration of NSCLC cells and regulates the expression of adhesion genes as part of a repressive complex. To further investigate this, we performed ChIP-Seq analysis to determine the enrichment of TIAM1, TRIM28 and H3K9me3 to chromatin in H441 cells.

2023-09-12 | GSE219029 | GEO

Investigating TIAM1 in NSCLC (RNA-Seq)

Project description:The T lymphoma invasion and metastasis inducing protein 1 (TIAM1) is a guanine nucleotide exchange factor (GEF) that activates the small GTPase RAC1. We have shown that nuclear TIAM1promotes the migration of NSCLC cells. To investigate the requirement for TIAM1 in regulating gene expression of NSCLC cells, we performed RNA-seq on H441 cells transfected with either siRNA for TIAM1 (siTIAM1) or a control siRNA (siControl) to identify differentially expressed genes.

2023-09-12 | GSE219028 | GEO

A TIAM1-TRIM28 complex mediates epigenetic silencing of protocadherins to promote migration of lung cancer cells

Project description:Lung cancer is the leading cause of cancer deaths. Its high mortality is associated with high metastatic potential. Here, we show that the RAC1-selective guanine nucleotide exchange factor T cell invasion and metastasis-inducing protein 1 (TIAM1) promotes cell migration and invasion in the most common subtype of lung cancer, non-small-cell lung cancer (NSCLC), through an unexpected nuclear function. We show that TIAM1 interacts with TRIM28, a master regulator of gene expression, in the nucleus of NSCLC cells. We reveal that a TIAM1-TRIM28 complex promotes epithelial-to-mesenchymal transition, a phenotypic switch implicated in cell migration and invasion. This occurs through H3K9me3-induced silencing of protocadherins and by decreasing E-cadherin expression, thereby antagonizing cell–cell adhesion. Consistently, TIAM1 or TRIM28 depletion suppresses the migration of NSCLC cells, while migration is restored by the simultaneous depletion of protocadherins. Importantly, high nuclear TIAM1 in clinical specimens is associated with advanced-stage lung adenocarcinoma, decreased patient survival, and inversely correlates with E-cadherin expression.

2023-09-12 | GSE219030 | GEO

The inhibitory effect of TIAM1 on TAZ transcriptional activity [ChIP-seq]

2017-04-26 | GSE90490 | GEO

List of TIAM1 differentially expressed genes in SW620 cells [RNA-seq]

Project description:The T lymphoma invasion and metastasis inducing protein 1 (TIAM1) is a guanine nucleotide exchange factor (GEF) that activates the small GTPase RAC1 and regulates a plethora of functions such as cell proliferation, migration, apoptosis and polarity. Recently, we demonstrated that TIAM1 shuttles between the cytoplasm and nucleus. To determine the nuclear role of TIAM1, we performed RNA-seq on SW620 cells transfected either with a specific pre-validated siRNA for TIAM1 (siTIAM1) or a negative control siRNA (siNT) and generated a list of TIAM1 differentially expressed genes. GSEA revealed significant enrichment among TIAM1-regulated genes for YAP-associated molecular signature. To investigate the interplay of TIAM1 with YAP/TAZ we used RNA-seq, generated a list of YAP/TAZ differentially expressed genes from SW620 cells transfected either with specific siRNAs for YAP/TAZ or a negative control siRNA and compared it with the siTIAM1 RNA-seq dataset. Interestingly, we found that 50% of the TAZ/YAP regulated genes were also TIAM1 dependent.

2017-04-26 | GSE90491 | GEO

Whole genome microarray of T lymphoma invasion and metastasis (Tiam1) silenced retinoblastoma Y79 cells

Project description:We hypothesized that Tiam1 is involved in invassiveness of retinoblastoma. The fuctional role of Tiam1 in cell progression and metastasis was tested by siRNA mediated knockdown of Tiam1 in retinoblastoma Y79 cells. The genes de-regulated in response to Tiam1 knockdown was analysed by cDNA microarray in which most of the actin cytoskeleton regulation proteins and apoptotic proteins were de-regulated. our results prove that Tiam1 modulates actin cytoskeleton and cell invasion in retinoblastoma. Retinoblastoma Y79 cells were treated with Tiam1 siRNA for 48hrs and cDNA microarray was performed to analyze the genes regulated by Tiam1 silencing compared to untreated Y79 cells. Experiments were performed in triplicates.

2013-03-31 | E-GEOD-45130 | biostudies-arrayexpress

Transcription profiling of primary human breast tumors showing poor clinical prognosis

Project description:Using microarray analysis, we identified a unique ras superfamily gene, termed RERG (ras-related and estrogen-regulated growth inhibitor), whose expression was decreased or lost in a significant percentage of primary human breast tumors that show a poor clinical prognosis. Importantly, high RERG expression correlated with expression of a set of genes that define a breast tumor subtype that is estrogen receptor-positive and associated with a slow rate of tumor cell proliferation and a favorable prognosis for these cancer patients. RERG mRNA expression was induced rapidly in MCF-7 cells stimulated by beta-estradiol and repressed by tamoxifen treatment. Like Ras, RERG protein exhibited intrinsic GDP/GTP binding and GTP hydrolysis activity. Unlike Ras proteins, RERG lacks a known recognition signal for COOH-terminal prenylation and was localized primarily in the cytoplasm. Expression of RERG protein in MCF-7 breast carcinoma cells resulted in a significant inhibition of both anchorage-dependent and anchorage-independent growth in vitro and inhibited tumor formation in nude mice. These features of RERG are strikingly different from most Ras superfamily GTP-binding pro-teins and suggest that the loss of RERG expression may contribute to breast tumorigenesis.

2005-06-22 | E-SMDB-1443 | biostudies-arrayexpress

Local GTP availability is an essential step in regulation of RAC1 activity and cell invasion

Project description:Physiological changes in GTP levels in live cells have never been considered a regulatory step of RAC1 activation because GTP concentrations determined by chromatography or mass spectrometry were shown to be substantially higher than the RAC1 GTP dissociation constant (RAC1-GTP Kd) determined in vitro. Here, using a combination of genetically engineered intracellular GTP sensors, recently generated by us, and RAC1 activity reporter, we demonstrate that fluctuations in GTP levels within the range of RAC1-GTP Kd, correlate with changes in RAC1 activity in live cells. We further demonstrate that RAC1 co-localize in protrusions of invading cells with the de novo guanylate biosynthesis enzymes including rate-limiting inosine monophosphate dehydrogenase 2 (IMPDH2) and guanosine monophosphate synthase (GMPS). This colocalization is partly driven by direct interaction of RAC1 with the Bateman domain of IMPDH2. Substitution of endogenous IMPDH2 with the IMPDH2 mutants incapable of binding RAC1 did not affect total intracellular GTP levels but suppressed RAC1 activity. Accordingly, targeting of IMPDH2 away from the plasma membrane did not alter total intracellular GTP pools but decreased local GTP levels in cell protrusions, downregulated RAC1 activity and decreased cell invasion. These data provide previously unrecognized mechanistic insight into the regulation of RAC1 activity by local GTP pools in live cells.

2021-11-04 | PXD028540 | Pride

RERG is a novel ras-related, estrogen-regulated and growth-inhibitory gene in breast cancer

2005-07-23 | E-GEOD-2987 | biostudies-arrayexpress

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