Journal
EBIOMEDICINE
Volume 45, Issue -, Pages 124-138Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ebiom.2019.06.051
Keywords
PLAGL2; POFUT1; Co-expression; Bidirectional promoter; Colorectal cancer; Cancer stem cell
Funding
- National Nature Science Foundation of China [81773130]
- Fundamental research funds for the Central Universities of Central South University (the Hunan province projects of Postgraduate Independent Exploration and Innovation of Central South University) [2018zzts050]
- New Xiangya Talent Projects of the Third Xiangya Hospital of Central South University [JY201508]
Ask authors/readers for more resources
Background: Our previous study revealed that PLAGL2 or POFUT1 can promote tumorigenesis and maintain significant positive correlations in colorectal cancer (CRC). However, the mechanism leading to the co-expression and the underlying functional and biological implications remain unclear. Methods: Clinical tumor tissues and TCGA dataset were utilized to analyze the co-expression of PLAGL2 and POFUT1. Luciferase reporter assays, specially made bidirectional promoter vectors and ectopic expression of 3'UTR were employed to study the mechanisms of co-expression. In vitro and in vivo assays were performed to further confirm the oncogenic function of both. The sphere formation assay, immunofluorescence, Western blot and qRT-PCR were performed to investigate the effect of both genes in colorectal cancer stem cells (CSCs). Findings: PLAGL2 and POFUT1 maintained co-expression in CRC (r = 0.91, p < .0001). An evolutionarily conserved bidirectional promoter, rather than post-transcriptional regulation by competing endogenous RNAs, caused the co-expression of PLAGL2 and POFUT1 in CRC. The bidirectional gene pair PLAGL2/POFUT1 was subverted in CRC and acted synergistically to promote colorectal tumorigenesis by maintaining stemness of colorectal cancer stem cells through the Wnt and Notch pathways. Finally, PLAGL2 and POFUT1 share transcription factor binding sites, and introducing mutations into promoter regions with shared transcription regulatory elements led to a decrease in the PLAGL2/POFUT1 promoter activity in both directions. Interpretation: Our team identified for the first time a bidirectional promoter pair oncogene, PLAGL2-POFUT1, in CRC. The two genes synergistically promote the progression of CRC and affect the characteristics of CSCs, which can offer promising intervention targets for clinicians and researchers. (C) 2019 The Authors. Published by Elsevier B.V.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available