WTAP promotes proliferation of esophageal squamous cell carcinoma via m 6 A-dependent epigenetic promoting of PTP4A1

• Published in: Cancer science 2024-07, Vol.115 (7), p.2254-2268
• Main Authors: Zou, Jiang, Ma, Qiang, Gao, Chuanli, Yang, Miyuan, Wen, Jilin, Xu, Lei, Guo, Xiaolan, Zhong, Xiaowu, Duan, Yixiang
• Format: Article
• Language: English
• Subjects: Adenosine - analogs & derivatives; Adenosine - metabolism; Animals; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Cell Proliferation - genetics; Epigenesis, Genetic; Esophageal Neoplasms - genetics; Esophageal Neoplasms - metabolism; Esophageal Neoplasms - pathology; Esophageal Squamous Cell Carcinoma - genetics; Esophageal Squamous Cell Carcinoma - metabolism; Esophageal Squamous Cell Carcinoma - pathology; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; Mice, Nude; Middle Aged; Proto-Oncogene Proteins c-akt - metabolism; RNA Splicing Factors; Signal Transduction - genetics; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Up-Regulation
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.15924

Esophageal squamous cell carcinoma (ESCC) represents a frequently seen malignancy with high prevalence worldwide. Although current studies have shown that Wilms' tumor 1-associated protein (WTAP), a major part in the methyltransferase complex, is involved in various tumor pathological processes, its specific role in ESCC remains unclear. Therefore, the present work focused on exploring WTAP's function and mechanism in ESCC progression using clinical ESCC specimens, ESCC cells, and mammalian models. Firstly, we proved WTAP was significantly upregulated within ESCC, and WTAP mRNA expression showed a good diagnostic performance for ESCC. Functionally, WTAP positively regulated in-vivo and in-vitro ESCC cells' malignant phenotype through the AKT-mTOR signaling pathway. Meanwhile, WTAP positively regulated the N6-methyladenosine (m A) modification levels in ESCC cells. Protein tyrosine phase type IVA member 1 (PTP4A1) was confirmed to be the m A target of WTAP, and WTAP positively regulated the expression of PTP4A1. Further study revealed that PTP4A1 showed high expression within ESCC. Silencing PTP4A1 inhibited the AKT-mTOR signaling pathway to suppress ESCC cells' proliferation. Rescue experiments showed that silencing PTP4A1 partially reversed the WTAP-promoting effect on ESCC cells' proliferation ability. Mechanistically, WTAP regulated PTP4A1 expression to activate the AKT-mTOR pathway, promoting the proliferation of ESCC cells. Our study demonstrated that WTAP regulates the progression of ESCC through the m A-PTP4A1-AKT-mTOR signaling axis and that WTAP is a potential target for diagnosing and treating ESCC.