DNMT3A facilitates colorectal cancer progression via regulating DAB2IP mediated MEK/ERK activation.

Abstract

The inactivation of tumor suppressor DOC-2/DAB2 interactive protein (DAB2IP) by epigenetic and post-transcriptional modification has been reported in multiple human malignancies. DNA methyltransferase 3A (DNMT3A) is involved in de novo establishment of DNA methylation and plays a vital role in tumorigenesis. However, whether DNMT3A can regulate colorectal cancer (CRC) progression via modulation of DAB2IP remains unclear. In this study, we revealed that DNMT3A was significantly increased in CRC, predicting a poor overall survival. Functionally, ectopic expression of DNMT3A in CRC cells enhanced cell proliferation, whereas DNMT3A knockdown had the opposite effect by inducing cell cycle arrest. Mechanistically, methylation-specific PCR (MSP) and bisulfite sequencing PCR (BSP) proved that the expression of DAB2IP was epigenetically suppressed by DNMT3A-mediated promoter methylation in CRC cells. Using dual-luciferase reporter assay and ChIP-PCR assay, we further confirmed that DNMT3A restrained the transcriptional activity of DAB2IP promoter through directly binging to it. In addition, DNMT3A could activate the MEK/ERK signaling pathway via efficiently downregulating DAB2IP. Inhibition of the MEK/ERK cascade abrogated the oncogenic effects of DNMT3A on CRC cells. In conclusion, our study demonstrates that DNMT3A facilitates CRC progression by regulating DAB2IP mediated MEK/ERK activation, providing promising targets for CRC treatment.