WTAP-mediated m6A methylation of circRNA_404908 promotes esophageal squamous cell carcinoma progression

Abstract

N6-methyladenosine (m⁶A) RNA methylation and circular RNA have been demonstrated to exert a crucial role in diverse malignant tumors, such as esophageal squamous cell carcinoma (ESCC). Nevertheless, the precise regulatory mechanism through which m⁶A-modified circRNA impacts ESCC remains to be elucidated. Herein, we discovered that the methyltransferase Wilms' tumor 1-associated protein (WTAP) is highly expressed in ESCC and is correlated with a poor prognosis. Knockdown of WTAP significantly diminishes the proliferation, migration, and invasion capabilities of ESCC cells both in vitro and in vivo. The m⁶A-circRNA epitranscriptomic microarray analysis, MeRIP-qPCR, RT-qPCR, and circularization verification ascertained that circRNA_404908 is the downstream target of WTAP. Knockdown of WTAP reduces the m⁶A level, expression, and stability of circRNA_404908. A series of functional assays indicate that circRNA_404908 facilitates the proliferation, migration, and invasion of ESCC cells, and overexpression of circRNA_404908 can counteract the reduction in cell proliferation, migration, and invasion abilities caused by si-WTAP. In addition, in vitro experiments demonstrated that circRNA_404908 regulates the expression of ANO1 by sponging miR-3059-5p, thereby promoting the progression of ESCC. Mechanistically, WTAP-mediated m⁶A modification of circRNA_404908 governs the miR-3059-5p/ANO1 axis to facilitate the advancement of ESCC. Collectively, our study reveals that WTAP-mediated m⁶A modification drives ESCC progression via circRNA_404908/miR-3059-5p/ANO1 axis, providing both mechanistic insights into m⁶A-circRNA crosstalk and potential therapeutic targets for ESCC treatment.

Keywords: ANO1; ESCC; WTAP; circRNA_404908; m(6)A; miR-3059-5p.