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PLAGL2 and POFUT1 are regulated by an evolutionarily conserved bidirectional promoter and are collaboratively involved in colorectal cancer by maintaining stemness.

Abstract：

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. FUND: National Nature Science Foundation of China, the Hunan province projects of Postgraduate Independent Exploration and Innovation of Central South University.

journal_name

EBioMedicine

journal_title

EBioMedicine

authors

Li D,Lin C,Li N,Du Y,Yang C,Bai Y,Feng Z,Su C,Wu R,Song S,Yan P,Chen M,Jain A,Huang L,Zhang Y,Li X

doi

10.1016/j.ebiom.2019.06.051

subject

Has Abstract

pub_date

2019-07-01 00:00:00

pages

124-138

issn

2352-3964

pii

S2352-3964(19)30432-3

journal_volume

45

pub_type

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