Back to Search
Start Over
N 6 -methyladenosine-Mediated Upregulation of WTAPP1 Promotes WTAP Translation and Wnt Signaling to Facilitate Pancreatic Cancer Progression.
- Source :
-
Cancer research [Cancer Res] 2021 Oct 15; Vol. 81 (20), pp. 5268-5283. Date of Electronic Publication: 2021 Aug 06. - Publication Year :
- 2021
-
Abstract
- Pseudogenes may play important roles in cancer. Here, we explore the mechanism and function of a pseudogene WTAPP1 in the progress of pancreatic ductal adenocarcinoma (PDAC). WTAPP1 RNA was significantly elevated in PDAC and was associated with poor prognosis in patients. Overexpression of WTAPP1 RNA promoted PDAC proliferation and invasiveness in vitro and in vivo . Mechanistically, N <superscript>6</superscript> -methyladenosine (m <superscript>6</superscript> A) modification stabilized WTAPP1 RNA via CCHC-type zinc finger nucleic-acid binding protein (CNBP), resulting in increased levels of WTAPP1 RNA in PDAC cells. Excessive WTAPP1 RNA bound its protein-coding counterpart WT1-associated protein (WTAP) mRNA and recruited more EIF3 translation initiation complex to promote WTAP translation. Increased WTAP protein enhanced the activation of Wnt signaling and provoked the malignant phenotypes of PDAC. Decreasing WTAPP1 RNA significantly suppressed the in vivo growth and metastasis of PDAC cell lines and patient-derived xenografts. These results indicate that m <superscript>6</superscript> A-mediated increases in WTAPP1 expression promote PDAC progression and thus may serve as a therapeutic target. SIGNIFICANCE: This study reveals how aberrant m <superscript>6</superscript> A modification of the WTAPP1 pseudogene results in increased translation of its protein-coding counterpart to promote Wnt signaling, which contributes to pancreatic cancer progression.<br /> (©2021 The Authors; Published by the American Association for Cancer Research.)
- Subjects :
- Adenosine chemistry
Animals
Apoptosis
Biomarkers, Tumor genetics
Biomarkers, Tumor metabolism
Carcinoma, Pancreatic Ductal genetics
Carcinoma, Pancreatic Ductal metabolism
Cell Cycle Proteins genetics
Cell Proliferation
Female
Gene Expression Regulation, Neoplastic
Humans
Mice
Mice, Inbred BALB C
Mice, Nude
Pancreatic Neoplasms genetics
Pancreatic Neoplasms metabolism
Prognosis
RNA Splicing Factors genetics
Survival Rate
Transcriptional Activation
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
Adenosine analogs & derivatives
Carcinoma, Pancreatic Ductal pathology
Cell Cycle Proteins metabolism
Pancreatic Neoplasms pathology
Protein Biosynthesis
RNA Splicing Factors metabolism
RNA, Long Noncoding genetics
Wnt Signaling Pathway
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 81
- Issue :
- 20
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 34362795
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-21-0494