The DNA Damage Transducer RNF8 Facilitates Cancer Chemoresistance and Progression through Twist Activation

Lee, Hong‐Jen; Li, Chien‐Feng; Ruan, Diane; Powers, Scott; Thompson, Patricia A.; Frohman, Michael A.; Chan, Chia‐Hsin

doi:10.1016/j.molcel.2016.08.009

Cited by 87 publications

(94 citation statements)

References 57 publications

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“…Extensive work has established the vital role of K63-Ub pathway in Akt oncogenic signaling and IKK β /NF κ B inflammation pathways [119, 120]. A recent report revealed an essential role for nonproteolytic Ub pathway in Twist activation and Twist-mediated EMT and CSC acquisition [121], suggesting that targeting the controlling E3 ligases for K63-linked Ub of EMT-TFs can be a potential approach for development of EMT/CSC-based new cancer therapeutics. It remains elusive whether and how this K63-linked Ub governs protein activity of major EMT-TFs other than Twist.…”

Section: Strategies and Current Advances In Targeting Emt-tfsmentioning

confidence: 99%

Tackling Cancer Stem Cells via Inhibition of EMT Transcription Factors

Mladinich

Ruan

Chan

2016

Stem Cells International

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Cancer stem cell (CSC) has become recognized for its role in both tumorigenesis and poor patient prognosis in recent years. Traditional therapeutics are unable to effectively eliminate this group of cells from the bulk population of cancer cells, allowing CSCs to persist posttreatment and thus propagate into secondary tumors. The therapeutic potential of eliminating CSCs, to decrease tumor relapse, has created a demand for identifying mechanisms that directly target and eliminate cancer stem cells. Molecular profiling has shown that cancer cells and tumors that exhibit the CSC phenotype also express genes associated with the epithelial-to-mesenchymal transition (EMT) feature. Ample evidence has demonstrated that upregulation of master transcription factors (TFs) accounting for the EMT process such as Snail/Slug and Twist can reprogram cancer cells from differentiated to stem-like status. Despite being appealing therapeutic targets for tackling CSCs, pharmacological approaches that directly target EMT-TFs remain impossible. In this review, we will summarize recent advances in the regulation of Snail/Slug and Twist at transcriptional, translational, and posttranslational levels and discuss the clinical implication and application for EMT blockade as a promising strategy for CSC targeting.

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Section: Strategies and Current Advances In Targeting Emt-tfsmentioning

confidence: 99%

Tackling Cancer Stem Cells via Inhibition of EMT Transcription Factors

Mladinich

Ruan

Chan

2016

Stem Cells International

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“…Depletion of RNF8 retains Ku80 on DNA and impairs NHEJ e ciency [36]. Recent study found that RNF8 facilities doxorubicin resistance in cancer stem cells [37]and radiation resistance in nasopharyngeal cancer, bladder cancer [38,39]. These studies prompt us to investigate the role of RNF8 in NHEJ in EC.…”

Section: Discussionmentioning

confidence: 99%

Targeting RNF8 Effectively Reverse Cisplatin and Doxorubicin Resistance in Endometrial Cancer

Yang

Wan

et al. 2020

Preprint

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Background Endometrial cancer (EC) is one of the most frequent gynecological malignancy worldwide. However, resistance to chemotherapy remains one of the major difficulties in the treatment of EC. Thus, there is an urgent requirement to understand mechanisms of chemoresistance and identify novel regimens for patients with EC. Methods Cisplatin and doxorubicin resistant cell lines were acquired by continuous exposing parental EC cells to cisplatin or doxorubicin for 3 months. Cell viability was determined by using MTT assay. Protein Expression levels of protein were examined by western blotting assay. mRNA levels were measured by quantitative polymerase chain reaction (qPCR) assay. Ring finger protein 8 (RNF8) knockout cell lines were generated by clustered regularly interspaced short palindromic repeats (CRISPR)–Cas9 gene editing assay. Nonhomologous end joining (NHEJ) efficiency were quantified by plasmid based NHEJ assay. DNA double strand breaks (DSB) were generated using laser micro-irradiation. Protein recruitment to DSB was analyzed by immunofluorescent assay. Tumor growth was examined by AN3CA xenograft mice model. Results We found that protein and mRNA expression levels of RNF8 were significantly increased in both cisplatin and doxorubicin resistant EC cells. Cell survival assay showed that RNF deficiency significantly enhanced the sensitivity of resistant EC cells to cisplatin and doxorubicin (P < 0.01). In addition, chemoresistant EC cells exhibited increased NHEJ efficiency. Knockout of RNF8 in chemoresistant EC cells significantly reduced NHEJ efficiency and prolonged Ku80 retention on DSB. Moreover, cisplatin resistant AN3CA xenograft showed that RNF8 deficiency overcame cisplatin resistance. Conclusions Our in vitro and in vivo assays provide evidence for RNF8, which is a NHEJ factor, serving as a promising, novel target in EC chemotherapy.

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“…23,24 Besides, DNA repair is closely coupled with cell survival. Weyemi et al 25 found that silencing H2A.X, an essential molecule involved in DNA repair, activated EMT transcription factors and increased tumor progression.…”

Section: Discussionmentioning

confidence: 99%

Transcriptome-wide elucidation of liposomal formulations for anticancer drug delivery

Liu¹,

Wang²,

Huang³

et al. 2017

IJN

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Although widely used in chemotherapy, free doxorubicin (Dox) might enhance cell malignancy undesirably. Liposomal Dox (Doxlipo) has been clinically approved for the treatment of breast cancer due to reduced systematical toxicity and increased tumor targeting, yet the transcriptome-wide elucidation of the Doxlipo formulations remains elusive. To this end, we explored the impact of two Dox liposomal formulations, Doxlipo mainly containing hydrogenated soy phosphatidylcholine or 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, on the transcriptional pattern of MCF-7 cells. The two types of Dox liposomal formulations with different drug release kinetics were investigated to reveal the relationship between the formulation and tumor malignancy. Interestingly, we found that liposomal formulation significantly altered the transcriptional pattern of a wide range of genes. Under equivalent dosage of Dox, free Dox substantially changed the expression of ANK1, ACTA2, GPR87, GDF15, FZD6, and WNT4 in MCF-7 cells. Notably, free Dox induced much higher expression of ABCB1 and significantly enhanced the cell migration behavior in comparison with HSPC Doxlipo under a similar level of cytotoxicity. Finally, siRNA targeting GPR87 was codelivered with cationic Doxlipo to reduce the expression of malignancy-related genes. Our study, for the first time, provides an overview of the influence of formulation on the malignancy at transcriptional level and reveals the relationship between cytotoxicity and cell malignancy from the formulation aspect, offering valuable reference for the future formulation design for anticancer drug delivery.

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The DNA Damage Transducer RNF8 Facilitates Cancer Chemoresistance and Progression through Twist Activation

Cited by 87 publications

References 57 publications

Tackling Cancer Stem Cells via Inhibition of EMT Transcription Factors

Tackling Cancer Stem Cells via Inhibition of EMT Transcription Factors

Targeting RNF8 Effectively Reverse Cisplatin and Doxorubicin Resistance in Endometrial Cancer

Transcriptome-wide elucidation of liposomal formulations for anticancer drug delivery

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