Activated MEK/ERK Pathway Drives Widespread and Coordinated Overexpression of UHRF1 and DNMT1 in Cancer cells

作者：Li, Jialun; Wang, Ruiping; Hu, Xueli; Gao, Yingying; Wang, Zhen; Li, Jiwen^*; Wong, Jiemin^*

来源：Scientific Reports, 2019, 9(1): 907.

DOI：10.1038/s41598-018-37258-3

• GLYCOGEN-SYNTHASE KINASE-3
• SIGNAL-REGULATED KINASE
• DNA METHYLTRANSFERASE-1
• GROUND-STATE
• PROTEIN-KINASE
• NAIVE PLURIPOTENCY
• GENE
• METHYLATION
• EXPRESSION
• ICBP90

The UHRF1-DNMT1 axis plays a key role in DNA maintenance methylation in mammals. Accumulative studies demonstrate that UHRF1 is broadly overexpressed in cancers, which contributes to cancer cell proliferation and tumorigenesis. Interestingly, a proteasome-dependent downregulation of UHRF1 has been observed in pluripotent ground state mouse embryonic stem cells (mESCs) cultured in the presence of two kinase (MEK1/MEK2 and GSK3 beta) inhibitors (termed 2i), raising the question whether UHRF1 is similarly regulated in cancer cells. Here we present evidence that while addition of 2i broadly downregulates UHRF1 and DNMT1 in various cancer cells, distinct underlying mechanisms are involved. In contrast to mESCs, 2i-induced downregulation of UHRF1 and DNMT1 in cancer cells cannot be rescued by proteasome inhibitor and occurs primarily at the level of transcription. Furthermore, downregulation of UHRF1 and DNMT1 by 2i is due to inhibition of MEK1/MEK2, but not GSK3 beta activity. Data mining reveals a marked co-expression of UHRF1 and DNMT1 in normal tissues as well as cancers. We provide evidence that multiple transcription factors including E2F1 and SP1 mediate the transcriptional activation of UHRF1 and DNMT1 by the activated MEK/ERK pathway. Together our study reveals distinct regulation of UHRF1/DNMT1 in mESCs and cancer cells and identifies activated MEK/ERK pathway as a driving force for coordinated and aberrant over-expression of UHRF1 and DNMT1 in cancers.

• 出版日期2019-1-29
• 单位华东师范大学