Cucurbitacin B-induced G2/M cell cycle arrest of conjunctival melanoma cells mediated by GRP78-FOXM1-KIF20A pathway
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA791241 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17288242_1.fastq.gz | Fastqsanger.gz | |||
| SRR17288242_2.fastq.gz | Fastqsanger.gz | |||
| SRR17288243_1.fastq.gz | Fastqsanger.gz | |||
| SRR17288243_2.fastq.gz | Fastqsanger.gz | |||
| SRR17288244_1.fastq.gz | Fastqsanger.gz |
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Project description:Conjunctival melanoma (CM) is a rare and fatal malignant eye tumor, it is life-threatening, mainly because of the lack of diagnostic biomarkers or drug access. In this study, we deciphered a novel anti-CM mechanism of a natural tetracyclic compound isolated from a Cucurbitaceae family plant and named as Cucurbitacin B (CuB). We found that CuB remarkably inhibited the proliferation of CRMM2 cells at a submicromolar level (IC50=0.15 μM) without toxicity to normal cells via G2/M cell cycle arrest and subsequent cell apoptosis. RNA-seq screening identified the Kinesin family member 20A (KIF20A) as a key gene which was abolished by the CuB treatment and proved to be a downstream effector of FOXM1 pathway. Further target identification by the activity-based protein profiling (ABPP) chemoproteomic approach revealed that 78 KDa Glucose-Regulated Protein (GRP78) is a potential target of CuB. Several lines of evidence demonstrated that CuB interacted with GRP78 and bound with a Kd value of 0.11 μM. Furthermore, functional experiments showed that CuB suppressed the ATPase activity of GRP78 both in human recombinant GRP78 and cellular lysates. Knockdown of the GRP78 gene significantly induced the downregulation of FOXM1 and related pathway genes including KIF20A, underlying an interesting therapeutic perspective. Taken together, our current work proved a substantial therapeutic potential of the traditional medicine CuB, and it needs to be explored further for future CM therapies.
2022-05-31 | GSE192359 | GEO
Project description:Conjunctival melanoma (CM) is a rare and fatal malignant eye tumor. In this study, we deciphered a novel anti-CM mechanism of a natural tetracyclic compound named as cucurbitacin B (CuB). We found that CuB remarkably inhibited the proliferation of CM cells including CM-AS16, CRMM1, CRMM2 and CM2005.1, without toxicity to normal cells. CuB can also induce CM cells G2/M cell cycle arrest. RNA-seq screening identified KIF20A, a key downstream effector of FOXM1 pathway, was abolished by CuB treatment. Further target identification by activity-based protein profiling chemoproteomic approach revealed that GRP78 is a potential target of CuB. Several lines of evidence demonstrated that CuB interacted with GRP78 and bound with a K d value of 0.11 μmol/L. Furthermore, ATPase activity evaluation showed that CuB suppressed GRP78 both in human recombinant GRP78 protein and cellular lysates. Knockdown of the GRP78 gene significantly induced the downregulation of FOXM1 and related pathway proteins including KIF20A, underlying an interesting therapeutic perspective. Finally, CuB significantly inhibited tumor progression in NCG mice without causing obvious side effects in vivo. Taken together, our current work proved that GRP78-FOXM1-KIF20A as a promising pathway for CM therapy, and the traditional medicine CuB as a candidate drug to hinder this pathway.
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Project description:Purpose：Forkhead box M1 (FOXM1) transcription factor is ubiquitously expressed in embryonic tissues but rare in differentiated cells. Increased expression of FOXM1 is observed in a variety of human malignancies. Here, we sought to characterize the expression and tumorigenic roles of FOXM1 in high-grade serous ovarian carcinoma (HGSOC). Experimental Design：TCGA dataset were analyed to identify potential master transcriptional regulators in HGSOC. Immunohistochemistry was performed to evaluate the clinical significance of FOXM1 in HGSOC. Invasion, clonogenic assays were conducted to determine to functional role of FOXM1. ChIP-seq and luciferase analyses were utilized to identify FOXM1 direct target genes in HGSOC. Association between mutant p53 and FOXM1 expression was investigated through TCGA data analysis, immunohistochemistry stainingand western blot. Results: We identified FOXM1 as a potential key transcription factor in ovarian cancer. FOXM1 was markedly increased in HGSOCs and high FOXM1 expression correlated with poor prognosis in HGSOC patients. Mechanistically, FOXM1 regulated CCNF and KIF20A at transcriptional level through binding on their promoters. Consistently, CCNF and KIF20A were elevated in HGSOCs and correlated with poor prognosis. Importantly, mutant p53 contribute to the high expression of FOXM1 in HGSOCs. Conclusions: These data reveal FOXM1 as a driver oncogenic transcription factor that promotes ovarian cancer malignancy which might be a potential drug target in HGSOC.
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Project description:Soft tissue sarcoma (STS) is a group of malignancies that can appear in any part of the body. The prognosis of STS patients remains unsatisfactory, mainly due to metastasis and recurrence. Upregulation of KIF20A is associated with poor prognosis of STS patients, but its downstream mechanism is unknown. In the present study, we found that downregulation of KIF20A in the STS cell line HT-1080 inhibits cell proliferation, migration, and invasion and induced cell apoptosis and G2/M arrest in vitro. In addition, downregulation of KIF20A in HT-1080 repressed tumorigenesis of STS in a xenograft mouse model. Pathway analysis showed, that downregulation of KIF20A led to suppression of downstream PI3K-AKT and NF-κB pathways. Specifically, the phosphorylation of AKT at Ser473 was inhibited. Taken together, our results indicate that KIF20A plays an important role in the development of STS by inhibiting cell proliferation, migration, invasion via the PI3K-AKT signaling pathway. Therefore, KIF20A is a potential therapeutic target in STS.
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Project description:Breast cancer stem cells (BCSCs), known to fuel TNBC malignancy, are now being exploited as the vulnerability for TNBC treatment. In this study, we dissected the transcriptome of BCSCs and identified Kinesin Family Member 20A (KIF20A) as an essential gene for BCSC survival and TNBC tumorigenesis. To understand the potential mechanism, we infected MDA-MB-231 cells with either control or V5-tagged KIF20A followed by V5 antibody pull down and mass spectrometry to identify KIF20A interaction proteins that may mediate its effect on gene regulation and TNBC cancer stem cell phenotype.
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