Phase separation of DDX21 promotes colorectal cancer metastasis via MCM5-dependent EMT pathway

Gao, Huabin; Wei, Huiting; Yang, Yang; Li, Hui; Liang, Jiangtao; Ye, Jiecheng; Zhang, Fenfen; Wang, Liyuan; Shi, Huijuan; Wang, Jia; Han, Anqin

doi:10.1038/s41388-023-02687-6

Cited by 26 publications

(8 citation statements)

References 54 publications

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“…26,27 Given the commonality of abnormal cell cycle regulation in tumors, targeting MCM5 function holds promise as a potential strategy to inhibit the excessive proliferation of tumor cells. 20,21,23,[28][29][30] Importantly, we first reported that MCM5 promotes glioma cell U87 and U251 proliferation and resistance to TMZ, aligning with previous research indicating its role in cisplatin resistance in head and neck squamous cell carcinoma. However, further studies with the incorporation of more cell lines are necessary to confirm this scenario.…”

Section: Discussionsupporting

confidence: 87%

“…15 It is a critical component of the CDC45-MCM-GINS helicase, a molecular apparatus responsible for unwinding template DNA during replication and serving as the foundation for the replisome. [16][17][18] Previous studies have found that MCM5 plays important roles in the progression of various cancers, including liver, lung, bladder, and colon cancers et al [19][20][21][22][23] Meanwhile, Jiang et al previously reported that the ubiquitination and degradation of MCM5 protein might impede the repair of DNA damage caused by cisplatin. 21 However, thus far, the expression, function and potential mechanisms of MCM5 in GBM chemotherapy resistance are still unclear.…”

Section: Introductionmentioning

confidence: 99%

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MCM5 is a Novel Therapeutic Target for Glioblastoma

Zhou,

Zheng,

Zhang

et al. 2024

OTT

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MCM5 is a DNA licensing factor involved in cell proliferation and has been previously established as an excellent biomarker in a number of malignancies. Nevertheless, the role of MCM5 in GBM has not been fully clarified. The present study aimed to investigate the potential roles of MCM5 in the treatment of GBM and to elucidate its underlying mechanism, which is beneficial for developing new therapeutic strategies and predicting prognosis. Methods: Firstly, we obtained transcriptomic and proteomic data from the TCGA and CPTAC databases on glioma patients. Employing the DeSeq2 R package, we then identified genes with joint differential expression in GBM tissues subjected to chemotherapy. To develop a prognostic risk score model, we performed univariate and multivariate Cox regression analyses. In vitro knockdown and overexpression of MCM5 were used to further investigate the biological functions of GBM cells. Additionally, we also delved into the upstream regulation of MCM5, revealing associations with several transcription factors. Finally, we investigated differences in immune cell infiltration and drug sensitivity across diverse risk groups identified in the prognostic risk model. Results: In this study, the chemotherapy-treated GBM samples exhibited consistent alterations in 46 upregulated and 94 downregulated genes at both the mRNA and protein levels. Notably, MCM5 emerged as a gene with prognostic significance as well as potential therapeutic relevance. In vitro experiments subsequently validated the role of increased MCM5 expression in promoting GBM cell proliferation and resistance to TMZ. Correlations with transcription factors such as CREB1, CTCF, NFYB, NRF1, PBX1, TEAD1, and USF1 were discovered during upstream regulatory analysis, enriching our understanding of MCM5 regulatory mechanisms. The study additionally delves into immune cell infiltration and drug sensitivity, providing valuable insights for personalized treatment approaches. Conclusion:This study identifies MCM5 as a key player in GBM, demonstrating its prognostic significance and potential therapeutic relevance by elucidating its role in promoting cell proliferation and resistance to chemotherapy.

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Section: Discussionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

MCM5 is a Novel Therapeutic Target for Glioblastoma

Zhou,

Zheng,

Zhang

et al. 2024

OTT

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“…Phase separation is the main mechanism for the formation of membraneless compartments in cells and is involved in the regulation of cellular metabolism, signal transduction, gene expression and protein homeostasis. In recent years, researchers have found that phase separation and cancer are closely linked, by affecting DNA repair processes, transcriptional regulation as well as the assembly of important membrane-free compartments in cancer [ 23 , 33 – 35 ].…”

Section: Resultsmentioning

confidence: 99%

EphA2 as a phase separation protein associated with ferroptosis and immune cell infiltration in colorectal cancer

Li,

Peng,

Wang

2023

Aging

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Colorectal cancer is one of the most common malignant tumors in the digestive system, and its high incidence and metastasis rate make it a terrible killer that threatens human health. In-depth exploration of the targets affecting the progression of colorectal cancer cells and the development of specific targeted drugs for them are of great significance for the prognosis of colorectal cancer patients. Erythropoietin-producing hepatocellular A2 (EphA2) is a member of the Eph subfamily with tyrosine kinase activity, plays a key role in the regulation of signaling pathways related to the malignant phenotype of various tumor cells, but its specific regulatory mechanism in colorectal cancer needs to be further clarified. Here, we found that EphA2 was abnormally highly expressed in colorectal cancer and that patients with colorectal cancer with high EphA2 expression had a worse prognosis. We also found that EphA2 can form liquid-liquid phase separation condensates on cell membrane, which can be disrupted by ALW-II-41-27, an inhibitor of EphA2. In addition, we found that EphA2 expression in colorectal cancer was positively correlated with the expression of ferroptosis-related genes and the infiltration of multiple immune cells. These findings suggest that EphA2 is a novel membrane protein with phase separation ability and is associated with ferroptosis and immune cell infiltration, which further suggests that malignant progression of colorectal cancer may be inhibited by suppressing the phase separation ability of EphA2.

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“…Similarly, another study revealed that the phase separation of DDX21 activates MCM5, thus triggering EMT signaling and modulating the colon cancer metastasis (Fig. 4 B)[ 143 ]. Besides, SGs are also involved in malignant invasion and metastasis.…”

Section: Deregulated Phase Separation In Cancermentioning

confidence: 90%

Phase separations in oncogenesis, tumor progressions and metastasis: a glance from hallmarks of cancer

Zheng,

Liu,

2023

J Hematol Oncol

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Liquid–liquid phase separation (LLPS) is a novel principle for interpreting precise spatiotemporal coordination in living cells through biomolecular condensate (BMC) formation via dynamic aggregation. LLPS changes individual molecules into membrane-free, droplet-like BMCs with specific functions, which coordinate various cellular activities. The formation and regulation of LLPS are closely associated with oncogenesis, tumor progressions and metastasis, the specific roles and mechanisms of LLPS in tumors still need to be further investigated at present. In this review, we comprehensively summarize the conditions of LLPS and identify mechanisms involved in abnormal LLPS in cancer processes, including tumor growth, metastasis, and angiogenesis from the perspective of cancer hallmarks. We have also reviewed the clinical applications of LLPS in oncologic areas. This systematic summary of dysregulated LLPS from the different dimensions of cancer hallmarks will build a bridge for determining its specific functions to further guide basic research, finding strategies to intervene in LLPS, and developing relevant therapeutic approaches.

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Phase separation of DDX21 promotes colorectal cancer metastasis via MCM5-dependent EMT pathway

Cited by 26 publications

References 54 publications

MCM5 is a Novel Therapeutic Target for Glioblastoma

MCM5 is a Novel Therapeutic Target for Glioblastoma

EphA2 as a phase separation protein associated with ferroptosis and immune cell infiltration in colorectal cancer

Phase separations in oncogenesis, tumor progressions and metastasis: a glance from hallmarks of cancer

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