Tumor suppressor FOXO3 regulates ribonucleotide reductase subunit RRM2B and impacts on survival of cancer patients
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Er-Chieh Cho1, Mei-Ling Kuo2, Xiyong Liu2, Lixin Yang2, Yi-Chen Hsieh3, Jinghan Wang4, Yawen Cheng5 and Yun Yen2
1 Department of Clinical Pharmacy, School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
2 Department of Molecular Pharmacology, Beckman Research Institute, City of Hope, Duarte, CA, USA
3 PhD Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
4 Department of Hepatobiliary Surgery, Navy General Hospital of Chinese PLA, Beijing, P. R. China
5 Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
Yun Yen, email:
Keywords: tumor suppressor FOXO3, RRM2B, cancer, biomarker
Received: May 24, 2014 Accepted: May 30, 2014 Published: May 31, 2014
The role of Ribonucleotide reductase (RR) subunits in different cancers has been intensively studied in our laboratory. RRM2B was identified as a p53-inducible RR subunit that involves in various critical cellular mechanisms such as cell cycle regulation, DNA repair and replication, and mitochondrial homeostasis, etc. However, little is known about the p53-independent regulation of RRM2B in cancer pathology. In this study, we discovered tumor suppressor FOXO3 as the novel regulator of RRM2B. FOXO3 directly bound to and transcriptionally activated the promoter of RRM2B, and induced the expression of RRM2B at RNA and protein levels. Moreover, Overexpression of RRM2B and/or FOXO3 inhibited the proliferation of cancer cells. The cancer tissue microarray data also demonstrated a strong correlation between the co-expression of FOXO3 plus RRM2B and increased disease survival and reduced recurrence or metastasis in lung cancer patients. Our results suggest a novel regulatory control of RRM2B function, and imply the importance of FOXO signaling pathway in DNA replication modulation. This study provides the first time evidence that RRM2B is transcriptionally and functionally regulated independent of p53 pathway by FOXO3, and it establishes that FOXO3 and RRM2B could be used as predictive biomarkers for cancer progression.
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