<i>N6</i> -methyladenosine–Mediated Upregulation of WTAPP1 Promotes WTAP Translation and Wnt Signaling to Facilitate Pancreatic Cancer Progression

Abstract

Pseudogenes may play important roles in cancer. Here, we explore the mechanism and function of a pseudogene <i>WTAPP1</i> in the progress of pancreatic ductal adenocarcinoma (PDAC). <i>WTAPP1</i> RNA was significantly elevated in PDAC and was associated with poor prognosis in patients. Overexpression of <i>WTAPP1</i> RNA promoted PDAC proliferation and invasiveness <i>in vitro</i> and <i>in vivo</i>. Mechanistically, <i>N</i> ⁶-methyladenosine (m⁶A) modification stabilized <i>WTAPP1</i> RNA via CCHC-type zinc finger nucleic-acid binding protein (CNBP), resulting in increased levels of <i>WTAPP1</i> RNA in PDAC cells. Excessive <i>WTAPP1</i> 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 <i>WTAPP1</i> RNA significantly suppressed the <i>in vivo</i> growth and metastasis of PDAC cell lines and patient-derived xenografts. These results indicate that m⁶A-mediated increases in <i>WTAPP1</i> expression promote PDAC progression and thus may serve as a therapeutic target. SIGNIFICANCE: This study reveals how aberrant m⁶A modification of the <i>WTAPP1</i> pseudogene results in increased translation of its protein-coding counterpart to promote Wnt signaling, which contributes to pancreatic cancer progression.