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RAD6 promotes DNA repair and stem cell signaling in ovarian cancer and is a promising therapeutic target to prevent and treat acquired chemoresistance

Somasagara, R. R., Spencer, S. M., Tripathi, K., Clark, D. W., Mani, C., Madeira da Silva, L., Scalici, J., Kothayer, H., Westwell, Andrew D., Rocconi, R. P. and Palle, K. 2017. RAD6 promotes DNA repair and stem cell signaling in ovarian cancer and is a promising therapeutic target to prevent and treat acquired chemoresistance. Oncogene 36 , pp. 6680-6690. 10.1038/onc.2017.279

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Abstract

Ovarian cancer (OC) is the most deadly gynecological cancer and unlike most other neoplasms, survival rates for OC have not significantly improved in recent decades. We show that RAD6, an ubiquitin-conjugating enzyme, is significantly overexpressed in ovarian tumors and its expression increases in response to carboplatin chemotherapy. RAD6 expression correlated strongly with acquired chemoresistance and malignant behavior of OC cells, expression of stem cell genes and poor prognosis of OC patients, suggesting an important role for RAD6 in ovarian tumor progression. Upregulated RAD6 enhances DNA damage tolerance and repair efficiency of OC cells and promotes their survival. Increased RAD6 levels cause histone 2B ubiquitination-mediated epigenetic changes that stimulate transcription of stem cell genes, including ALDH1A1 and SOX2, leading to a cancer stem cell phenotype, which is implicated in disease recurrence and metastasis. Downregulation of RAD6 or its inhibition using a small molecule inhibitor attenuated DNA repair signaling and expression of cancer stem cells markers and sensitized chemoresistant OC cells to carboplatin. Together, these results suggest that RAD6 could be a therapeutic target to prevent and treat acquired chemoresistance and disease recurrence in OC and enhance the efficacy of standard chemotherapy.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Publisher: Nature Publishing Group
ISSN: 0950-9232
Date of First Compliant Deposit: 30 August 2017
Date of Acceptance: 7 July 2017
Last Modified: 02 Jul 2019 05:38
URI: http://orca-mwe.cf.ac.uk/id/eprint/104102

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