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Supplementary Figures from N6-methyladenosine–Mediated Upregulation of WTAPP1 Promotes WTAP Translation and Wnt Signaling to Facilitate Pancreatic Cancer Progression

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posted on 2023-04-01, 00:21 authored by Junge Deng, Jialiang Zhang, Ying Ye, Kaijing Liu, Lingxing Zeng, Jingyi Huang, Ling Pan, Mei Li, Ruihong Bai, Lisha Zhuang, Xudong Huang, Guandi Wu, Lusheng Wei, Yanfen Zheng, Jiachun Su, Shaoping Zhang, Rufu Chen, Dongxin Lin, Jian Zheng

Supplementary Figure S1-S6 and corresponding Supplementary Figure legends

Funding

National Natural Science Foundation of China (NSFC)

Natural Science Foundation of Guangdong Province (Guangdong Natural Science Foundation)

Program for Guangdong Introducing Innovative and Entrepreneurial Teams

National Young Top-notch Talent Support Program

Sun Yat-sen University Intramural Funds

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ARTICLE 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, N6-methyladenosine (m6A) 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 m6A-mediated increases in WTAPP1 expression promote PDAC progression and thus may serve as a therapeutic target. This study reveals how aberrant m6A modification of the WTAPP1 pseudogene results in increased translation of its protein-coding counterpart to promote Wnt signaling, which contributes to pancreatic cancer progression.

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