High migration and invasion ability of PGCCs and their daughter cells associated with the nuclear localization of S100A10 modified by SUMOylation
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ABSTRACT:
PROVIDER: PRJNA735527 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14743656_1.fastq.gz | Fastqsanger.gz | |||
| SRR14743656_2.fastq.gz | Fastqsanger.gz | |||
| SRR14743657_1.fastq.gz | Fastqsanger.gz | |||
| SRR14743657_2.fastq.gz | Fastqsanger.gz | |||
| SRR14743658_1.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: S100A10 uesed to located in the cell membrane or cytoplasm. However nuclear-located S100A10 was observed in the polyploid tumor giant cells(PGCCs) with daughter cells induced by cobalt chloride(CoCl2). To study the function of nuclear-located S100A10, we performed ChIP-Seq. Methods:LoVo and Hct116 cells were incubated in T25 flasks in RPMI-1640 medium until they reached 80-90% confluence. The cells were treated with 450 μM CoCl2 (Sigma-Aldrich, St. Louis, MO, USA) for 48-72h based on their resistance to hypoxia. After the treatment with CoCl2 was repeated for 3-4 times, there were 20-30% of PGCCs and 70-80% of small-sized daughter cells that originated from PGCCs among the total cells.ChIP assays were performed according to the instructions of the Pierce Magnetic ChIP Kit (Thermo Fisher Scientific, #26157) For data analysis of ChIP DNA, sequencing and library preparation were performed using Novogene Technology Co., Ltd. (Tianjin, China). Raw data (raw reads) of FASTQ format were first processed through in-house PERL scripts, and then reference genome and gene model annotation files were downloaded directly from the genome website. For a specific ChIP-seq binding site, individual reads were mapped to the plus or minus strand and presented significant enrichment. After mapping the reads to the reference genome, the MACS2 version 2.1.0 (model-based analysis of ChIP-seq) peak finding algorithm was used to identify regions of specific IP enrichment over background. A p-value threshold of enrichment of 0.05 was used for all data sets. The interaction between transcription factor or chromatin histone modification and DNA was not random, but they showed some specific sequence preference. MEME 52 and DREME 53 were used to detect the sequence motif, which was used to detect long and short consensus sequences. The position of peak summit around the transcript start sites of genes can predict the interaction sites of proteins and genes. Genes associated with different peaks were identified, and GO and KEGG enrichment analyses were performed. Results:The results showed that 4148 significant ChIP-seq peaked in Hct116-derived PGCCs with daughter cells, and 1380 peaked in LoVo-derived PGCCs with daughter cells. Genes with overlapping peaks were then enriched by Gene Ontology [GO], which revealed that these genes participated in various processes including stimulus, cell migration, and cell motility.Moreover, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed the potential targets involved in metabolic pathways, axon guidance TGF-β signaling pathway, and so on. Conclusions: S100A10 can be modified by SUMOylation in PGCCs and their daughter cells induced by either CoCl2 or chemotherapeutic drugs. SUMO1-modified S100A10 can translocate to the nucleus and regulate the expression of ARHGEF18, PTPRN2, and DEFA3 to promote the proliferation, migration, and invasion of PGCCs and their daughter cells, which may contribute to the poor prognosis in patients with cancer. The discovery of detailed mechanisms of the S100A10 SUMOylation, such as the specific lysine sites involved in SUMOylation and which SUMO E3 ligase regulates the SUMOylation of S100A10 requires further study.
2021-06-07 | GSE176231 | GEO
Project description:Our previous studies have confirmed that cobalt chloride (CoCl2) or chemoradiotherapy could induce the formation of polyploid tumor giant cells (PGCCs). Polyploid giant cancer cells are a special subpopulation of cancer cells that contribute to solid tumor heterogeneity. The size of PGCC was at least three times larger than regular diploid cancer cells. PGCCs have the properties of cancer stem cells (CSCs) and can express CSC markers CD44 and CD133. Daughter cells derived from PGCCs have strong proliferation, infiltration and migration abilities. However, the detailed molecular mechanism of daughter cells expressing mesenchymal phenotype and displaying strong abilities of proliferation and migration is unclear. As a plasminogen receptor, S100A10 which is closely associated with the invasion and metastasis of malignant tumors, was highly expressed in PGCCs with their daughter cells. In this study, CoCl2 was used to induce the formation of PGCCs in LoVo and HCT116 CRC cells. Cell functional experiments, co-immunoprecipitation, MG132 and ginkgolic acid treatment, western blot, and ChIP-Seq were used to identify the mechanism of S100A10 nuclear location. The proliferation and migration abilities of PGCCs and their daughter cells decreased significantly after S100A10 knockdown. In the control cells, S100A10 was mainly ubiquitinated, while in PGCCs and daughter cells, S100A10 was mainly SUMOylated, which was associated with S100A10 nuclear location. After SUMO1 was inhibited, the nuclear S100A10 in PGCCs and daughter cells decreased, and their proliferation and migration abilities significantly decreased. ChIP-Seq combined with real-time fluorescent quantitative PCR showed that S100A10 regulated the expression of neutrophil defensin 3 (DEFA3), receptor-type tyrosine-protein phosphatase N2 (PTPRN2), and rho guanine nucleotide exchange factor 18 (ARHGEF18), which were associated with actin dynamics and cytoskeleton remodeling. The expression of S100A10 in the nuclei and cytoplasm of rectal cancer after neoadjuvant chemoradiation (nCRT) and liver metastases increased compared with that in rectal cancer without nCRT. Taken together, the expression and nuclear localization of S100A10 modified by SUMOylation were associated with the high proliferation and migration of PGCCs and their daughter cells, and the differentiation, metastases, and relapse of CRCs by regulating the expression of ARHGEF18, PTPRN2, and DEFA3.
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Project description:Genome wide localization of SUMO1 and SUMO2/3 proteins revealed an asscociation of SUMO proetins with active chromatin. SUMO proteins are enriched at super enhancers and enhancers and SUMOylation regulates a subset of these super enhancers. Super enhancers regulated by SUMOylation were enriched for transcription factor TFAP2C and SUMOylation negatively regulates TFAP2C localization to enhancers and super enhancers. Proteomics and ChIP-PCR at MYC SE suggests that chromatin bound TFAP2C recruits histone deacetylation complexes that increases upon SAE2 knockdown. Conversely, SUMOylation promoted TFAP2C asscociation with pre-mRNA splicing machinery components. Taken together, our study revealed a critical role of SUMOylation in chromatin modification through an AP-2 family of transcription factor, TFAP2C and a potential role of TFAP2C in pre-mRNA splicing.
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Project description:Genome wide localization of SUMO1 and SUMO2/3 proteins revealed an asscociation of SUMO proetins with active chromatin. SUMO proteins are enriched at super enhancers and enhancers and SUMOylation regulates a subset of these super enhancers. Super enhancers regulated by SUMOylation were enriched for transcription factor TFAP2C and SUMOylation negatively regulates TFAP2C localization to enhancers and super enhancers. Proteomics and ChIP-PCR at MYC SE suggests that chromatin bound TFAP2C recruits histone deacetylation complexes that increases upon SAE2 knockdown. Conversely, SUMOylation promoted TFAP2C asscociation with pre-mRNA splicing machinery components. Taken together, our study revealed a critical role of SUMOylation in chromatin modification through an AP-2 family of transcription factor, TFAP2C and a potential role of TFAP2C in pre-mRNA splicing.
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Project description:Gastric cancer (GC) remains a significant health challenge due to its high mortality rate and the limited efficacy of current targeted therapies. A critical barrier in developing more effective treatments is the lack of understanding of specific mechanisms driving GC progression. This study investigates the role of Transient Receptor Potential Vanilloid 1 (TRPV1), a non-selective cation channel known for its high Ca2+ permeability and tumor-suppressive properties in gastrointestinal cancers. Specifically, we explore the impact of SUMOylation—a dynamic and reversible post-translational modification—on TRPV1's function in GC. We demonstrate that SUMOylation of TRPV1 inhibits cell proliferation and migration in MGC-803 and AGS gastric cancer cells. By mutating amino acids near TRPV1's existing SUMO motif (slKpE), we created a bidirectional SUMO motif (EψKψE) that enhances TRPV1 SUMOylation, resulting in further suppression of GC cell proliferation and migration. In vivo studies support these findings, showing that TRPV1 SUMOylation prevents spontaneous tumorigenesis in a mouse gastric cancer model. Further investigation reveals that TRPV1 SUMOylation increases the protein's membrane expression by inhibiting its interaction with the adaptor-related protein complex 2 mu 1 subunit (AP2M1). This elevated membrane expression leads to increased intracellular Ca2+ influx, activating the AMP-activated protein kinase (AMPK) pathway, which in turn inhibits the proliferation and migration of GC cells. In conclusion, our study elucidates a novel mechanism wherein TRPV1 SUMOylation promotes its membrane expression and activates the TRPV1-Ca2+-AMPK signaling pathway, thereby inhibiting GC cell proliferation and migration. These findings enhance our understanding of the molecular dynamics in gastric cancer and could provide a new theoretical basis for clinical treatment strategies.
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Project description:SUMOylation-Induced Membrane Localization of TRPV1 Suppresses Proliferation and Migration in Gastric Cancer Cells
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Project description:Phylogenetically conserved lysines 419 and 845 of zebrafish Zbtb21 protein can be conjugated with SUMO molecules. SUMOylation does not affect the subcellular localization and protein stability of Zbtb21, as well as the interaction with Zbtb14 or Zbtb21. Nevertheless, luciferase reporter assays revealed that Zbtb21 is a dual-function transcription factor which exerts activation or repression effect on different promoters, and SUMOylation can modulate the transcriptional activity of Zbtb21 in regulating downstream target genes. Hence, Zbtb21 is identified as a novel substrate of SUMOylation, which would be important for its function.
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