Regulation of coactivator-associated arginine methyltransferase-1 by dual specificity phosphatase-2 in colorectal cancer

摘要

Colorectal cancer is a common malignant disease and the third leading cause of cancer death in the world Although intensive efforts have been devoted to investigate the pathogenesis of colorectal cancer the exact molecular mechanisms involved in the process remain largely unknown Coactivator-associated arginine methyltransferase 1 (CARM1) a member of protein arginine methyltransferase family catalyzes asymmetric methylation of the arginine (Arg) residues in protein substrates According to the published literatures CARM1 involves in multiple important biological processes such us gene regulation cell-cycle progression and the DNA damage response However the mechanism of CARM1 action remains obscure in cancer To characterize whether the expression of CARM1 contributes to the development of colorectal cancer we first evaluated the level of CARM1 in the colorectal cancer specimens from the public datasets Our data demonstrated that CARM1 expression was up regulated in colorectal cancer and negatively associated with poor survival Similar results were also observed in our own colorectal cancer samples Next to demonstrate whether the CARM1 expression affects cellular function CARM1 was knocked down by siRNA in colorectal cancer cell line and its cellular functions were evaluated Cell proliferation and migration assays demonstrated that knockdown of CARM1 significantly repressed cell proliferative and migratory abilities To further investigate the underlying mechanism causing CARM1 overexpression in colorectal cancer we identified EGR-1 binding sites located in the CARM1 promoter region through bioinformatics analysis Since our previous data demonstrated that EGR-1expression was negatively regulated by Dual Specificity Phosphatase 2 (DUSP2) we thus hypothesized that loss of DUSP2 may cause CARM1 overexpression via EGR-1-mediated gene transcription To test the idea DUSP2 was knocked down by siRNA in colorectal cancer cells Knockdown of DUSP2 indeed caused an increase of CARM1 expression Similar results were observed in the intestine tissues from DUSP2 conditional knockout mice and supported by the clinical specimen analysis In summary we have found that loss of DUSP2 results in CARM1 overexpression which promotes pathological processes of colorectal cancer

獎項日期	2018 8月 28
原文	English
監督員	Shaw-Jenq Tsai (Supervisor)