CREB1 directly activates the transcription of ribonucleotide reductase small subunit M2 and promotes the aggressiveness of human colorectal cancer.

Zejun Fang,Hong Liu,Aifen Lin,Jiaoe Chen,Jiangang Zhang,Lanlan Qiu,Xiang Chen,Lingming Mei,Xiaomin Zhang,Yanyan Hu,Jimin Shao,Hongzhang Li,Xia Zhang

doi:10.18632/oncotarget.12938

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.

Highlights

As an enzyme of central importance in DNA synthesis, Ribonucleotide reductase (RR) plays a crucial role in various biological processes by catalyzing the de novo conversion of ribonucleoside diphosphates to deoxyribonucleoside diphosphates [1]
To test whether the correlation extended to the mRNA level, three colorectal cancer (CRC) cell lines were transfected with cAMP responsive element binding protein 1 (CREB1) small interfering RNA (siRNA) and the mRNA levels of RRM2 were measured
These results suggested that the expression of RRM2 is activated by CREB1 in CRC cells

Summary

Introduction

As an enzyme of central importance in DNA synthesis, Ribonucleotide reductase (RR) plays a crucial role in various biological processes by catalyzing the de novo conversion of ribonucleoside diphosphates to deoxyribonucleoside diphosphates [1]. The RR holoenzyme is composed of two identical large subunits (RRM1) and two identical small subunits (RRM2 or RRM2B). RRM1–RRM2 holoenzyme is necessary for S-phase DNA replication and repair in proliferating cells, whereas RRM1–RRM2B provides dNTPs for DNA repair in quiescent cells as well as mtDNA replication and repair [3,4,5]. Due to that RRM1 remains constant throughout the cell cycle owing to its long halflife, the activity of RR is modulated by levels of the small subunits (RRM2 or RRM2B), expressions of which are tightly regulated during the cell cycle [6,7,8]. Several www.impactjournals.com/oncotarget transcription factors such as E2F, are responsible for S phase induced transcription of RRM2 while p53 is known as a novel activator of RRM2B in response to DNA damage [10,11,12]

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Conclusion