DNA Replication Licensing Factors: Novel Targets for Cancer Therapy via Inhibiting the Stemness of Cancer Cells

Song, Shaoran; Wang, Yao-Chun; Liu, Peijun

doi:10.7150/ijbs.67529

Cited by 9 publications

(4 citation statements)

References 89 publications

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“…It was identified that HCT116 colon cancer cells initiate DNA replication normally in the absence of ORC5 and ORC2 proteins [ 88 ]. Additionally, ORC2 was associated with prevention of apoptosis induction and could serve as a potential target for cancer therapy by inhibition of cancer cell stemness [ 89 ].…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics Analysis of RNA-seq Data Reveals Genes Related to Cancer Stem Cells in Colorectal Cancerogenesis

Urh

Zidar

Boštjančič

2022

IJMS

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Cancer stem cells (CSC) play one of the crucial roles in the pathogenesis of various cancers, including colorectal cancer (CRC). Although great efforts have been made regarding our understanding of the cancerogenesis of CRC, CSC involvement in CRC development is still poorly understood. Using bioinformatics and RNA-seq data of normal mucosa, colorectal adenoma, and carcinoma (n = 106) from GEO and TCGA, we identified candidate CSC genes and analyzed pathway enrichment analysis (PEI) and protein–protein interaction analysis (PPI). Identified CSC-related genes were validated using qPCR and tissue samples from 47 patients with adenoma, adenoma with early carcinoma, and carcinoma without and with lymph node metastasis and were compared to normal mucosa. Six CSC-related genes were identified: ANLN, CDK1, ECT2, PDGFD, TNC, and TNXB. ANLN, CDK1, ECT2, and TNC were differentially expressed between adenoma and adenoma with early carcinoma. TNC was differentially expressed in CRC without lymph node metastases whereas ANLN, CDK1, and PDGFD were differentially expressed in CRC with lymph node metastases compared to normal mucosa. ANLN and PDGFD were differentially expressed between carcinoma without and with lymph node metastasis. Our study identified and validated CSC-related genes that might be involved in early stages of CRC development (ANLN, CDK1, ECT2, TNC) and in development of metastasis (ANLN, PDGFD).

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Section: Discussionmentioning

confidence: 99%

Bioinformatics Analysis of RNA-seq Data Reveals Genes Related to Cancer Stem Cells in Colorectal Cancerogenesis

Urh

Zidar

Boštjančič

2022

IJMS

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“… 219 , 220 (b) Aberrant DNA replication license system induces abnormal DNA replication, increasing genomic instability, and carcinogenesis. 221 , 222 In addition, spontaneous mutation of MCMs increases chromosome elimination and DNA damage, 223 whereas a more than twofold reduction of MCM protein expression could lead to genomic instability in S. cerevisiae . These findings demonstrated that MCMs are indeed involved in tumorigenesis, but the detailed mechanism is still unclear.…”

Section: Dna Replication Disease and Therapymentioning

confidence: 99%

“…However, dysregulation of the cell cycle‐dependent kinase CDK permits MCMs constantly binding to each other, resulting in continuous cell division and high expression 219,220 . (b) Aberrant DNA replication license system induces abnormal DNA replication, increasing genomic instability, and carcinogenesis 221,222 . In addition, spontaneous mutation of MCMs increases chromosome elimination and DNA damage, 223 whereas a more than twofold reduction of MCM protein expression could lead to genomic instability in S. cerevisiae .…”

Section: Dna Replication Disease and Therapymentioning

confidence: 99%

DNA replication: Mechanisms and therapeutic interventions for diseases

Song

Shen

Mahasin

et al. 2023

MedComm

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Accurate and integral cellular DNA replication is modulated by multiple replication-associated proteins, which is fundamental to preserve genome stability. Furthermore, replication proteins cooperate with multiple DNA damage factors to deal with replication stress through mechanisms beyond their role in replication. Cancer cells with chronic replication stress exhibit aberrant DNA replication and DNA damage response, providing an exploitable therapeutic target in tumors. Numerous evidence has indicated that posttranslational modifications (PTMs) of replication proteins present distinct functions in DNA replication and respond to replication stress. In addition, abundant replication proteins are involved in tumorigenesis and development, which act as diagnostic and prognostic biomarkers in some tumors, implying these proteins act as therapeutic targets in clinical. Replication-target cancer therapy emerges as the times require. In this context, we outline the current investigation of the DNA replication mechanism, and simultaneously enumerate the aberrant expression of replication proteins as hallmark for various diseases, revealing their therapeutic potential for target therapy. Meanwhile, we also discuss current observations that the novel PTM of replication proteins in response to replication stress, which seems to be a promising strategy to eliminate diseases.

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“…Three complexes with ubiquitin ligase activity are responsible for inhibiting CDT1 activity, namely SKP1cullin-1-F-box protein containing SKP2 complex (SCF SKP2 ), denticleless E3 ubiquitin protein ligase homolog CUL4-DDB1 CDT2 and the anaphase-promoting complex/cyclosome-CDH1 (APC/C) CDH1 complex (13,17). Several studies have shown that deregulation of DNA replication-licensing factors is significantly implicated in cancer (18)(19)(20). Overexpression of CDT1 has been reported to promote carcinogenesis through increased genomic instability (14,21,22).…”

mentioning

confidence: 99%

CUL4A Ubiquitin Ligase Is an Independent Predictor of Overall Survival in Pancreatic Adenocarcinoma

TAVLAS,

NIKOU,

GERAMOUTSOU

et al. 2024

Cancer Genomics Proteomics

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Background/Aim: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with dismal prognosis. Genomic instability due to defects in cell-cycle regulation/mitosis or deficient DNA-damage repair is a major driver of PDAC progression with clinical relevance. Deregulation of licensing of DNA replication leads to DNA damage and genomic instability, predisposing cells to malignant transformation. While overexpression of DNA replicationlicensing factors has been reported in several human cancer types, their role in PDAC remains largely unknown. We aimed here to examine the expression and prognostic significance of the DNA replication-licensing factors chromatin licensing and DNA replication factor 1 (CDT1), cell-division cycle 6 (CDC6), minichromosome maintenance complex component 7 (MCM7) and also of the ubiquitin ligase regulator of CDT1, cullin 4A (CUL4A), in PDAC. Materials and Methods: Expression levels of CUL4, CDT1, CDC6 and MCM7 were evaluated by immunohistochemistry in 76 formalin-fixed paraffin-embedded specimens of PDAC patients in relation to DNA-damage response marker H2AX, clinicopathological parameters and survival. We also conducted bioinformatics analysis of data from online available databases to corroborate our findings.

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DNA Replication Licensing Factors: Novel Targets for Cancer Therapy via Inhibiting the Stemness of Cancer Cells

Cited by 9 publications

References 89 publications

Bioinformatics Analysis of RNA-seq Data Reveals Genes Related to Cancer Stem Cells in Colorectal Cancerogenesis

Bioinformatics Analysis of RNA-seq Data Reveals Genes Related to Cancer Stem Cells in Colorectal Cancerogenesis

DNA replication: Mechanisms and therapeutic interventions for diseases

CUL4A Ubiquitin Ligase Is an Independent Predictor of Overall Survival in Pancreatic Adenocarcinoma

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