FAT1 inhibits the proliferation of DLBCL cells via increasing the m 6 A modification of YAP1 mRNA

• Published in: Scientific reports 2024-05, Vol.14 (1), p.11836
• Main Authors: Wang, Tian-Long, Miao, Xiao-Juan, Shuai, Yan-Rong, Sun, Hao-Ping, Wang, Xiao, Yang, Min, Zhang, Nan
• Format: Article
• Language: English
• Subjects: 3' Untranslated Regions; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Adenosine - analogs & derivatives; Adenosine - metabolism; Cadherins - genetics; Cadherins - metabolism; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Humans; Lymphoma, Large B-Cell, Diffuse - genetics; Lymphoma, Large B-Cell, Diffuse - metabolism; Lymphoma, Large B-Cell, Diffuse - pathology; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction; Transcription Factors - genetics; Transcription Factors - metabolism; YAP-Signaling Proteins - genetics; YAP-Signaling Proteins - metabolism
• ISSN: 2045-2322
• DOI: 10.1038/s41598-024-62793-7

Emerging evidence shows that FAT atypical cadherin 1 (FAT1) mutations occur in lymphoma and are associated with poorer overall survival. Considering that diffuse large B cell lymphoma (DLBCL) is the category of lymphoma with the highest incidence rate, this study aims to explore the role of FAT1 in DLBCL. The findings demonstrate that FAT1 inhibits the proliferation of DLBCL cell lines by downregulating the expression of YAP1 rather than by altering its cellular localization. Mechanistic analysis via meRIP-qPCR/luciferase reporter assays showed that FAT1 increases the m A modification of YAP1 mRNA 3'UTR and the subsequent binding of heterogeneous nuclear ribonucleoprotein D (HNRNPD) to the m A modified YAP1 mRNA, thus decreasing the stability of YAP1 mRNA. Furthermore, FAT1 increases YAP1 mRNA 3'UTR m A modification by decreasing the activity of the TGFβ-Smad2/3 pathway and the subsequent expression of ALKBH5, which is regulated at the transcriptional level by Smad2/3. Collectively, these results reveal that FAT1 inhibits the proliferation of DLBCL cells by increasing the m A modification of the YAP1 mRNA 3'UTR via the TGFβ-Smad2/3-ALKBH5 pathway. The findings of this study therefore indicate that FAT1 exerts anti-tumor effects in DLBCL and may represent a novel target in the treatment of this form of lymphoma.