CARF enrichment promotes epithelial–mesenchymal transition via Wnt/β-catenin signaling: its clinical relevance and potential as a therapeutic target
Abstract CARF (Collaborator of ARF)/CDKN2AIP was discovered as a novel ARF-binding protein. It has been established as an essential cell survival, p53-, and cell proliferation-regulatory protein. Although a moderate upregulation of CARF caused growth arrest and senescence, its excessively enriched l...
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doaj-b4d23cae745945dca9f26c3a217729d82020-12-07T23:30:46ZengNature Publishing GroupOncogenesis2157-90242018-05-017511310.1038/s41389-018-0048-4CARF enrichment promotes epithelial–mesenchymal transition via Wnt/β-catenin signaling: its clinical relevance and potential as a therapeutic targetRajkumar S. Kalra0Anupama Chaudhary1A-Rum Yoon2Priyanshu Bhargava3Amr Omar4Sukant Garg5Chae-Ok Yun6Sunil C. Kaul7Renu Wadhwa8Drug Discovery and Assets Innovation Lab, DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), DAICENTER, National Institute of Advanced Industrial Science & Technology (AIST)Drug Discovery and Assets Innovation Lab, DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), DAICENTER, National Institute of Advanced Industrial Science & Technology (AIST)Department of Bioengineering, College of Engineering, Hanyang UniversityDrug Discovery and Assets Innovation Lab, DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), DAICENTER, National Institute of Advanced Industrial Science & Technology (AIST)Drug Discovery and Assets Innovation Lab, DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), DAICENTER, National Institute of Advanced Industrial Science & Technology (AIST)Drug Discovery and Assets Innovation Lab, DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), DAICENTER, National Institute of Advanced Industrial Science & Technology (AIST)Department of Bioengineering, College of Engineering, Hanyang UniversityDrug Discovery and Assets Innovation Lab, DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), DAICENTER, National Institute of Advanced Industrial Science & Technology (AIST)Drug Discovery and Assets Innovation Lab, DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), DAICENTER, National Institute of Advanced Industrial Science & Technology (AIST)Abstract CARF (Collaborator of ARF)/CDKN2AIP was discovered as a novel ARF-binding protein. It has been established as an essential cell survival, p53-, and cell proliferation-regulatory protein. Although a moderate upregulation of CARF caused growth arrest and senescence, its excessively enriched levels were shown to facilitate aggressive proliferation and malignant transformation of cancer cells. Here, we examined the relevance of CARF levels in clinical tumors and found its amplification (both at gene and transcript levels) in a variety of invasive and metastatic malignancies. Consistent with the clinical readouts, enrichment of CARF in cancer cells promoted epithelial–mesenchymal transition (EMT). Cancer database and molecular analyses revealed that it activates Wnt/β-catenin signaling axis, as evident by enhanced nuclear localization and function of β-catenin marked by increased level of SNAIL1, SNAIL2, ZEB1, and TWIST1 and its downstream gene targets. Of note, targeted knockdown of CARF led to decrease in nuclear β-catenin and its key downstream effectors, involved in EMT progression. Consistent with this, CARF targeting in vivo either by naked siRNA or CARF shRNA harboring adeno-oncolytic virus caused suppression of tumor progression and lung metastasis. Taken together, we report clinical and therapeutic relevance of CARF in EMT and cancer invasiveness/metastasis, and propose it as a potent therapeutic target of aggressive cancers.https://doi.org/10.1038/s41389-018-0048-4 |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Rajkumar S. Kalra Anupama Chaudhary A-Rum Yoon Priyanshu Bhargava Amr Omar Sukant Garg Chae-Ok Yun Sunil C. Kaul Renu Wadhwa |
spellingShingle |
Rajkumar S. Kalra Anupama Chaudhary A-Rum Yoon Priyanshu Bhargava Amr Omar Sukant Garg Chae-Ok Yun Sunil C. Kaul Renu Wadhwa CARF enrichment promotes epithelial–mesenchymal transition via Wnt/β-catenin signaling: its clinical relevance and potential as a therapeutic target Oncogenesis |
author_facet |
Rajkumar S. Kalra Anupama Chaudhary A-Rum Yoon Priyanshu Bhargava Amr Omar Sukant Garg Chae-Ok Yun Sunil C. Kaul Renu Wadhwa |
author_sort |
Rajkumar S. Kalra |
title |
CARF enrichment promotes epithelial–mesenchymal transition via Wnt/β-catenin signaling: its clinical relevance and potential as a therapeutic target |
title_short |
CARF enrichment promotes epithelial–mesenchymal transition via Wnt/β-catenin signaling: its clinical relevance and potential as a therapeutic target |
title_full |
CARF enrichment promotes epithelial–mesenchymal transition via Wnt/β-catenin signaling: its clinical relevance and potential as a therapeutic target |
title_fullStr |
CARF enrichment promotes epithelial–mesenchymal transition via Wnt/β-catenin signaling: its clinical relevance and potential as a therapeutic target |
title_full_unstemmed |
CARF enrichment promotes epithelial–mesenchymal transition via Wnt/β-catenin signaling: its clinical relevance and potential as a therapeutic target |
title_sort |
carf enrichment promotes epithelial–mesenchymal transition via wnt/β-catenin signaling: its clinical relevance and potential as a therapeutic target |
publisher |
Nature Publishing Group |
series |
Oncogenesis |
issn |
2157-9024 |
publishDate |
2018-05-01 |
description |
Abstract CARF (Collaborator of ARF)/CDKN2AIP was discovered as a novel ARF-binding protein. It has been established as an essential cell survival, p53-, and cell proliferation-regulatory protein. Although a moderate upregulation of CARF caused growth arrest and senescence, its excessively enriched levels were shown to facilitate aggressive proliferation and malignant transformation of cancer cells. Here, we examined the relevance of CARF levels in clinical tumors and found its amplification (both at gene and transcript levels) in a variety of invasive and metastatic malignancies. Consistent with the clinical readouts, enrichment of CARF in cancer cells promoted epithelial–mesenchymal transition (EMT). Cancer database and molecular analyses revealed that it activates Wnt/β-catenin signaling axis, as evident by enhanced nuclear localization and function of β-catenin marked by increased level of SNAIL1, SNAIL2, ZEB1, and TWIST1 and its downstream gene targets. Of note, targeted knockdown of CARF led to decrease in nuclear β-catenin and its key downstream effectors, involved in EMT progression. Consistent with this, CARF targeting in vivo either by naked siRNA or CARF shRNA harboring adeno-oncolytic virus caused suppression of tumor progression and lung metastasis. Taken together, we report clinical and therapeutic relevance of CARF in EMT and cancer invasiveness/metastasis, and propose it as a potent therapeutic target of aggressive cancers. |
url |
https://doi.org/10.1038/s41389-018-0048-4 |
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