Hypomethylation of GDNF family receptor alpha 1 promotes epithelial-mesenchymal transition and predicts metastasis of colorectal cancer.

Abstract

Tumor metastasis is the major cause of poor prognosis and mortality in colorectal cancer (CRC). However, early diagnosis of highly metastatic CRC is currently difficult. In the present study, we screened for a novel biomarker, GDNF family receptor alpha 1 (GFRA1) based on the expression and methylation data in CRC patients from The Cancer Genome Altlas (TCGA), followed by further analysis of the correlation between the GFRA1 expression, methylation, and prognosis of patients. Our results show DNA hypomethylation-mediated upregulation of GFRA1 in invasive CRC, and it was found to be correlated with poor prognosis of CRC patients. Furthermore, GFRA1 methylation-modified sequences were found to have potential as methylation diagnostic markers of highly metastatic CRC. The targeted demethylation of GFRA1 by dCas9-TET1CD and gRNA promoted CRC metastasis in vivo and in vitro. Mechanistically, demethylation of GFRA1 induces epithelial-mesenchymal transition (EMT) by promoting AKT phosphorylation and increasing c-Jun expression in CRC cells. Collectively, our findings indicate that GFRA1 hypomethylation can promote CRC invasion via inducing EMT, and thus, GFRA1 methylation can be used as a biomarker for the early diagnosis of highly metastasis CRC.

• Authors: Zhexu Dong, Lei Dai, Yong Zhang, Chao Fang, Gang Shi, Ye Chen, Junshu Li, Qin Wang, Jiamei Fu, Yan Yu, Wenshuang Wang, Lin Cheng, Yi Liu, Yi Lin, Yuan Wang, Qingnan Wang, Huiling Wang, Hantao Zhang, Yujing Zhang, Xiaolan Su, Shuang Zhang, Feng Wang, Meng Qiu, Zongguang Zhou, Hongxin Deng
• Journal: PLoS genetics (PLoS Genet) Vol. 16 Issue 11 Pg. e1009159 (11 2020) ISSN: 1553-7404 [Electronic] United States
• PMID: 33175846 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor
• GFRA1 protein, human
• Glial Cell Line-Derived Neurotrophic Factor Receptors
• JUN protein, human
• Proto-Oncogene Proteins c-jun
• AKT1 protein, human
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Biomarkers, Tumor (genetics)
• Cell Proliferation (genetics)
• Cohort Studies
• Colorectal Neoplasms (diagnosis, genetics, mortality, pathology)
• Computational Biology
• DNA Demethylation
• DNA Methylation
• Datasets as Topic
• Disease-Free Survival
• Epithelial-Mesenchymal Transition (genetics)
• Female
• Gene Expression Regulation, Neoplastic
• Glial Cell Line-Derived Neurotrophic Factor Receptors (genetics)
• HCT116 Cells
• HT29 Cells
• Humans
• Lung Neoplasms (genetics, secondary)
• Mice
• Neoplasm Invasiveness (genetics)
• Phosphorylation (genetics)
• Prognosis
• Proto-Oncogene Proteins c-akt (metabolism)
• Proto-Oncogene Proteins c-jun (metabolism)
• RNA-Seq
• Up-Regulation
• Xenograft Model Antitumor Assays