Human helicase RECQL4 drives cisplatin resistance in gastric cancer by activating an AKT-YB1-MDR1 signaling pathway
Elevation of the DNA-unwinding helicase RECQL4, which participates in various DNA repair pathways, has been suggested to contribute to the pathogenicity of various human cancers, including gastric cancer. In this study, we addressed the prognostic and chemotherapeutic significance of RECQL4 in human...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
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American Association for Cancer Research
2016
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| Online Access: | https://eprints.nottingham.ac.uk/43059/ |
| _version_ | 1848796629583265792 |
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| author | Mo, Dongliang Fang, Hongbo Niu, Kaifeng Liu, Jing Wu, Meng Li, Shiyou Zhu, Tienian Aleskandarany, Mohammed A. Arora, Arvind Lobo, Dileep N. Madhusudan, Srinivasan Balajee, Adayabalam S. Chi, Zhenfen Zhao, Yongliang |
| author_facet | Mo, Dongliang Fang, Hongbo Niu, Kaifeng Liu, Jing Wu, Meng Li, Shiyou Zhu, Tienian Aleskandarany, Mohammed A. Arora, Arvind Lobo, Dileep N. Madhusudan, Srinivasan Balajee, Adayabalam S. Chi, Zhenfen Zhao, Yongliang |
| author_sort | Mo, Dongliang |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | Elevation of the DNA-unwinding helicase RECQL4, which participates in various DNA repair pathways, has been suggested to contribute to the pathogenicity of various human cancers, including gastric cancer. In this study, we addressed the prognostic and chemotherapeutic significance of RECQL4 in human gastric cancer, which has yet to be determined. We observed significant increases in RECQL4 mRNA or protein in >70% of three independent sets of human gastric cancer specimens examined, relative to normal gastric tissues. Strikingly, high RECQL4 expression in primary tumors correlated well with poor survival and gastric cancer lines with high RECQL4 expression displayed increased resistance to cisplatin treatment. Mechanistic investigations revealed a novel role for RECQL4 in transcriptional regulation of the multidrug resistance gene MDR1, through a physical interaction with the transcription factor YB1. Notably, ectopic expression of RECQL4 in cisplatin-sensitive gastric cancer cells with low endogenous RECQL4 was sufficient to render them resistant to cisplatin, in a manner associated with YB1 elevation and MDR1 activation. Conversely, RECQL4 silencing in cisplatin-resistant gastric cancer cells with high endogenous RECQL4 suppressed YB1 phosphorylation, reduced MDR1 expression, and resensitized cells to cisplatin. In establishing RECQL4 as a critical mediator of cisplatin resistance in gastric cancer cells, our findings provide a therapeutic rationale to target RECQL4 or the downstream AKT-YB1-MDR1 axis to improve gastric cancer treatment. |
| first_indexed | 2025-11-14T19:51:01Z |
| format | Article |
| id | nottingham-43059 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T19:51:01Z |
| publishDate | 2016 |
| publisher | American Association for Cancer Research |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-430592020-05-04T17:43:48Z https://eprints.nottingham.ac.uk/43059/ Human helicase RECQL4 drives cisplatin resistance in gastric cancer by activating an AKT-YB1-MDR1 signaling pathway Mo, Dongliang Fang, Hongbo Niu, Kaifeng Liu, Jing Wu, Meng Li, Shiyou Zhu, Tienian Aleskandarany, Mohammed A. Arora, Arvind Lobo, Dileep N. Madhusudan, Srinivasan Balajee, Adayabalam S. Chi, Zhenfen Zhao, Yongliang Elevation of the DNA-unwinding helicase RECQL4, which participates in various DNA repair pathways, has been suggested to contribute to the pathogenicity of various human cancers, including gastric cancer. In this study, we addressed the prognostic and chemotherapeutic significance of RECQL4 in human gastric cancer, which has yet to be determined. We observed significant increases in RECQL4 mRNA or protein in >70% of three independent sets of human gastric cancer specimens examined, relative to normal gastric tissues. Strikingly, high RECQL4 expression in primary tumors correlated well with poor survival and gastric cancer lines with high RECQL4 expression displayed increased resistance to cisplatin treatment. Mechanistic investigations revealed a novel role for RECQL4 in transcriptional regulation of the multidrug resistance gene MDR1, through a physical interaction with the transcription factor YB1. Notably, ectopic expression of RECQL4 in cisplatin-sensitive gastric cancer cells with low endogenous RECQL4 was sufficient to render them resistant to cisplatin, in a manner associated with YB1 elevation and MDR1 activation. Conversely, RECQL4 silencing in cisplatin-resistant gastric cancer cells with high endogenous RECQL4 suppressed YB1 phosphorylation, reduced MDR1 expression, and resensitized cells to cisplatin. In establishing RECQL4 as a critical mediator of cisplatin resistance in gastric cancer cells, our findings provide a therapeutic rationale to target RECQL4 or the downstream AKT-YB1-MDR1 axis to improve gastric cancer treatment. American Association for Cancer Research 2016-05-01 Article PeerReviewed Mo, Dongliang, Fang, Hongbo, Niu, Kaifeng, Liu, Jing, Wu, Meng, Li, Shiyou, Zhu, Tienian, Aleskandarany, Mohammed A., Arora, Arvind, Lobo, Dileep N., Madhusudan, Srinivasan, Balajee, Adayabalam S., Chi, Zhenfen and Zhao, Yongliang (2016) Human helicase RECQL4 drives cisplatin resistance in gastric cancer by activating an AKT-YB1-MDR1 signaling pathway. Cancer Research, 76 (10). pp. 3057-3066. ISSN 1538-7445 http://cancerres.aacrjournals.org/content/76/10/3057.long doi:10.1158/0008-5472.CAN-15-2361 doi:10.1158/0008-5472.CAN-15-2361 |
| spellingShingle | Mo, Dongliang Fang, Hongbo Niu, Kaifeng Liu, Jing Wu, Meng Li, Shiyou Zhu, Tienian Aleskandarany, Mohammed A. Arora, Arvind Lobo, Dileep N. Madhusudan, Srinivasan Balajee, Adayabalam S. Chi, Zhenfen Zhao, Yongliang Human helicase RECQL4 drives cisplatin resistance in gastric cancer by activating an AKT-YB1-MDR1 signaling pathway |
| title | Human helicase RECQL4 drives cisplatin resistance in gastric cancer by activating an AKT-YB1-MDR1 signaling pathway |
| title_full | Human helicase RECQL4 drives cisplatin resistance in gastric cancer by activating an AKT-YB1-MDR1 signaling pathway |
| title_fullStr | Human helicase RECQL4 drives cisplatin resistance in gastric cancer by activating an AKT-YB1-MDR1 signaling pathway |
| title_full_unstemmed | Human helicase RECQL4 drives cisplatin resistance in gastric cancer by activating an AKT-YB1-MDR1 signaling pathway |
| title_short | Human helicase RECQL4 drives cisplatin resistance in gastric cancer by activating an AKT-YB1-MDR1 signaling pathway |
| title_sort | human helicase recql4 drives cisplatin resistance in gastric cancer by activating an akt-yb1-mdr1 signaling pathway |
| url | https://eprints.nottingham.ac.uk/43059/ https://eprints.nottingham.ac.uk/43059/ https://eprints.nottingham.ac.uk/43059/ |