Targeting YTHDF2 inhibits tumorigenesis of diffuse large B-cell lymphoma through ACER2-mediated ceramide catabolism.

in Journal of advanced research by Xiaomin Chen, Tiange Lu, Mengfei Ding, Yiqing Cai, Zhuoya Yu, Xiangxiang Zhou, Xin Wang

TLDR

  • This study investigates the role of YTHDF2 in DLBCL and how it affects lipid metabolism. The study found that YTHDF2 is highly expressed in DLBCL and related to poor prognosis. YTHDF2 overexpression exerts a tumor-promoting effect in DLBCL, while knockdown of YTHDF2 restricts DLBCL cell proliferation and enhances drug sensitivity. The study also identified a regulatory role of YTHDF2 in ceramide metabolism in DLBCL cells, with exogenous ceramide inhibiting the malignant phenotype of DLBCL cells in vitro. The study provides insights into targeted therapies and suggests that ceramide metabolism may be a promising therapeutic target in DLBCL.

Abstract

Epigenetic alterations play crucial roles in diffuse large B-cell lymphoma (DLBCL). Disturbances in lipid metabolism contribute to tumor progression. However, studies in epigenetics, especially its critical regulator YTH N6-methyladenosine RNA binding protein 2 (YTHDF2), on lipid metabolism regulation in DLBCL are unidentified. Elucidate the prognostic value and biological functions of YTHDF2 in DLBCL and illuminate the underlying epigenetic regulation mechanism of lipid metabolism by YTHDF2 in DLBCL development. The expression and clinical value of YTHDF2 in DLBCL were performed in public databases and clinical specimens. The biological functions of YTHDF2 in DLBCL were determined in vivo and in vitro through overexpression and CRISPR/Cas9-mediated knockout of YTHDF2. RNA sequencing, lipidomics, methylated RNA immunoprecipitation sequencing, RNA immunoprecipitation-qPCR, luciferase activity assay, and RNA stability experiments were used to explore the potential mechanism by which YTHDF2 contributed to DLBCL progression. YTHDF2 was highly expressed in DLBCL, and related to poor prognosis. YTHDF2 overexpression exerted a tumor-promoting effect in DLBCL, and knockdown of YTHDF2 restricted DLBCL cell proliferation, arrested cell cycle in the G2/M phase, facilitated apoptosis, and enhanced drug sensitivity to ibrutinib and venetoclax. In addition, YTHDF2 knockout drastically suppressed tumor growth in xenograft DLBCL models. Furthermore, a regulatory role of YTHDF2 in ceramide metabolism was identified in DLBCL cells. Exogenous ceramide effectively inhibited the malignant phenotype of DLBCL cells in vitro. The binding of YTHDF2 to m6A sites on alkaline ceramidase 2 (ACER2) mRNA promoted its stability and expression. Enhanced ACER2 expression hydrolyzed ceramides, disrupting the balance between ceramide and sphingosine-1-phosphate (S1P), activating the ERK and PI3K/AKT pathways, and leading to DLBCL tumorigenesis. This study demonstrated that YTHDF2 contributed to the progression of DLBCL by regulating ACER2-mediated ceramide metabolism in an m6A-dependent manner, providing novel insights into targeted therapies.

Overview

  • The study investigates the role of YTHDF2 in DLBCL and its impact on lipid metabolism regulation. The study uses public databases and clinical specimens to determine the expression and clinical value of YTHDF2 in DLBCL. In vivo and in vitro experiments are conducted to explore the biological functions of YTHDF2 in DLBCL. The study aims to elucidate the prognostic value and underlying epigenetic regulation mechanism of YTHDF2 in DLBCL development.

Comparative Analysis & Findings

  • YTHDF2 is highly expressed in DLBCL and related to poor prognosis. YTHDF2 overexpression exerts a tumor-promoting effect in DLBCL, while knockdown of YTHDF2 restricts DLBCL cell proliferation, arrests cell cycle in the G2/M phase, facilitates apoptosis, and enhances drug sensitivity to ibrutinib and venetoclax. YTHDF2 knockout drastically suppresses tumor growth in xenograft DLBCL models. The study identifies a regulatory role of YTHDF2 in ceramide metabolism in DLBCL cells, with exogenous ceramide inhibiting the malignant phenotype of DLBCL cells in vitro. The binding of YTHDF2 to m6A sites on ACER2 mRNA promotes its stability and expression, leading to DLBCL tumorigenesis through the activation of the ERK and PI3K/AKT pathways.

Implications and Future Directions

  • The study highlights the importance of YTHDF2 in DLBCL progression and provides insights into targeted therapies. Future research should focus on the development of YTHDF2-targeted therapies and the exploration of other epigenetic regulators of lipid metabolism in DLBCL. The study also suggests that ceramide metabolism may be a promising therapeutic target in DLBCL.
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