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

Xiaomin Chen; Tiange Lu; Mengfei Ding; Yiqing Cai; Zhuoya Yu; Xiangxiang Zhou; Xin Wang

doi:10.1016/j.jare.2023.10.010

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

J Adv Res. 2023 Oct 19:S2090-1232(23)00314-4. doi: 10.1016/j.jare.2023.10.010. Online ahead of print.

Authors

Xiaomin Chen¹, Tiange Lu¹, Mengfei Ding¹, Yiqing Cai¹, Zhuoya Yu¹, Xiangxiang Zhou², Xin Wang³

Affiliations

¹ Department of Hematology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong 250021, China.
² Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Suzhou 251006, China. Electronic address: xiangxiangzhou@sdu.edu.cn.
³ Department of Hematology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong 250021, China; Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Branch of National Clinical Research Center for Hematologic Diseases, Jinan, Shandong 250021, China; National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Suzhou 251006, China. Electronic address: xinw007@126.com.

PMID: 37865189
DOI: 10.1016/j.jare.2023.10.010

Abstract

Introduction: 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.

Objectives: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: ACER2; Ceramide; DLBCL; Tumorigenesis; YTHDF2.