title: CREB1 directly activates the transcription of ribonucleotide reductase small subunit M2 and promotes the aggressiveness of human colorectal cancer.
abstract: 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.
authors: Central Laboratory, Sanmen People's Hospital of Zhejiang, Sanmen, Zhejiang, 317100, China.
authors: Zejun
authors: Z
authors: Fang
authors: Human Tissue Bank, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, 317000, China.
authors: Aifen
authors: A
authors: Lin
authors: Central Laboratory, Sanmen People's Hospital of Zhejiang, Sanmen, Zhejiang, 317100, China.
authors: Jiaoe
authors: J
authors: Chen
authors: Central Laboratory, Sanmen People's Hospital of Zhejiang, Sanmen, Zhejiang, 317100, China.
authors: Xiaomin
authors: X
authors: Zhang
authors: Zhejiang Normal University - Jinhua People's Hospital Joint Center for Biomedical Research, Jinhua, Zhejiang, 321004, China.
authors: Hong
authors: H
authors: Liu
authors: Central Laboratory, Sanmen People's Hospital of Zhejiang, Sanmen, Zhejiang, 317100, China.
authors: Hongzhang
authors: H
authors: Li
authors: Central Laboratory, Sanmen People's Hospital of Zhejiang, Sanmen, Zhejiang, 317100, China.
authors: Yanyan
authors: Y
authors: Hu
authors: Human Tissue Bank, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, 317000, China.
authors: Xia
authors: X
authors: Zhang
authors: Human Tissue Bank, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, 317000, China.
authors: Jiangang
authors: J
authors: Zhang
authors: Central Laboratory, Sanmen People's Hospital of Zhejiang, Sanmen, Zhejiang, 317100, China.
authors: Lanlan
authors: L
authors: Qiu
authors: Central Laboratory, Sanmen People's Hospital of Zhejiang, Sanmen, Zhejiang, 317100, China.
authors: Lingming
authors: L
authors: Mei
authors: Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China.
authors: Jimin
authors: J
authors: Shao
authors: Central Laboratory, Sanmen People's Hospital of Zhejiang, Sanmen, Zhejiang, 317100, China.
authors: Xiang
authors: X
authors: Chen
mesh_terms: D000368:Aged; D000818:Animals; D049109:Cell Proliferation / Q000502:physiology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics* / Q000378:metabolism; D005260:Female; D045325:HCT116 Cells; D019073:HT29 Cells; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D012262:Ribonucleoside Diphosphate Reductase / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
chemical_list: C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; C093713:ribonucleotide reductase M2; D012262:Ribonucleoside Diphosphate Reductase
keywords: CREB1; aggressiveness; colorectal cancer; ribonucleotide reductase small subunit M2