Research Article Open Access

Elevated Glucose Promotes DNA Replication and Cancer Cell Growth through pRB-E2F1

Abstract

Although epidemiological studies have highlighted a link between hyperglycemia and increased risk of cancer, knowledge about the molecular mechanism behind the link remains limited. Moreover, while High Glucose (HG) is known to promote cell growth, the overall transcription regulation involved in this process is less clear. In this study, through genome-wide analyses, we identify E2F1 as the core transcription factor for the HG-induced cell growth. Inhibition of E2F1 abrogates the HG-induced DNA synthesis and cell growth, supporting the role of E2F1 in this process. Furthermore, we demonstrate that elevated glucose levels enhance pRB phosphorylation, which plays a role in E2F1 activation. Interestingly, among HG-induced E2F1 target genes, RRM2 (Ribonucleotide Reductase regulatory subunit M2) participates in the nucleotide synthesis by catalyzing the generation of the essential dNTP for DNA replication. We show that HG increases cellular dNTP levels in E2F1-RRM2 dependent manner, which correlates to enhanced DNA synthesis and cancer cell growth. Collectively, our findings decipher a pRB-E2F1-RRM2 dependent link between hyperglycemia and cancer cell proliferation and provide a molecular mechanism by which hyperglycemia directs tumor cells to DNA replication.

Qi Zhou, Dongmei Bai, Jacob Schrier, Xuan Liu*

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