WTAP Mediated m6A Modification Stabilizes PDIA3P1 and Promotes Tumor Progression Driven by Histone Lactylation in Esophageal Squamous Cell Carcinoma

Abstract

Esophageal squamous cell carcinoma (ESCC) is a common digestive tract malignant cancer with high incidence and mortality rate. Many studies have shown that long noncoding RNAs (lncRNAs are involved in the progression of various types of tumors. The lncRNA protein disulfide isomerase family A member 3 pseudogene 1 (PDIA3P1) promotes the progression of ESCC, but the molecular mechanism behind this is still unclear. In this study, PDIA3P1 is highly expressed in ESCC, produces more lactate by regulating glycolysis, and the increased lactate upregulates lactylation levels to drive tumor progression. Mechanistically, PDIA3P1 competes with miR-152-3p to prevent degradation of glucose transporter 1 (GLUT1) mRNA, and disrupts the binding between membrane-associated RING-CH 8 (MARCH8) and hexokinase 2 (HK2) to reduce ubiquitination degradation of HK2, thereby promoting glycolysis. High activity glycolysis produces more lactate, which upregulates the level of histone H4K8 lactylation (H4K8la) and promotes the transcription of target bone morphogenic protein 7 (BMP7). Functionally, BMP7 is involved in the regulation of ESCC progression by PDIA3P1 both in vivo and in vitro. In addition, wilms tumor 1-associated protein (WTAP) mediated m6A modification enhances the stability of PDIA3P1 through Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) dependent recognition. Taken together, these findings reveal the key role of PDIA3P1 regulates glycolysis-H4K8la-BMP7 axis in the progression of ESCC and provides new insights into the interplay between metabolic reprogramming and epigenetic regulation.

Keywords: N6‐methyladenosine; PDAI3P1; esophageal squamous cell carcinoma; glycolysis; histone lactylation.