CREB1 directly activates the transcription of ribonucleotide reductase small subunit M2 and promotes the aggressiveness of human colorectal cancer
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Zejun Fang1, Aifen Lin2, Jiaoe Chen1, Xiaomin Zhang1, Hong Liu3, Hongzhang Li1, Yanyan Hu1, Xia Zhang2, Jiangang Zhang2, Lanlan Qiu1, Lingming Mei1, Jimin Shao4, Xiang Chen1
1Central Laboratory, Sanmen People’s Hospital of Zhejiang, Sanmen, Zhejiang, 317100, China
2Human Tissue Bank, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, 317000, China
3Zhejiang Normal University - Jinhua People’s Hospital Joint Center for Biomedical Research, Jinhua, Zhejiang, 321004, China
4Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China
Xiang Chen, email: [email protected]
Jimin Shao, email: [email protected]
Keywords: CREB1, ribonucleotide reductase small subunit M2, aggressiveness, colorectal cancer
Received: March 16, 2016 Accepted: October 17, 2016 Published: October 27, 2016
As the small subunit of Ribonucleotide reductase (RR), RRM2 displays a very important role in various critical cellular processes such as cell proliferation, DNA repair, and senescence, etc. Importantly, RRM2 functions like a tumor driver in most types of cancer but little is known about the regulatory mechanism of RRM2 in cancer development. In this study, we found that the cAMP responsive element binding protein 1 (CREB1) acted as a transcription factor of RRM2 gene in human colorectal cancer (CRC). CREB1 directly bound to the promoter of RRM2 gene and induced its transcriptional activation. Knockdown of CREB1 decreased the expression of RRM2 at both mRNA and protein levels. Moreover, knockdown of RRM2 attenuated CREB1-induced aggressive phenotypes of CRC cells in vitro and in vivo. Analysis of the data from TCGA database and clinical CRC specimens with immunohistochemical staining also demonstrated a strong correlation between the co-expression of CREB1 and RRM2. Decreased disease survivals were observed in CRC patients with high expression levels of CREB1 or RRM2. Our results indicate CREB1 as a critical transcription factor of RRM2 which promotes tumor aggressiveness, and imply a significant correlation between CREB1 and RRM2 in CRC specimens. These may provide the possibility that CREB1 and RRM2 could be used as biomarkers or targets for CRC diagnosis and treatment.
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