LRPPRC promotes glycolysis by stabilising LDHA mRNA and its knockdown plus glutamine inhibitor induces synthetic lethality via m 6 A modification in triple‐negative breast cancer

作者：Yuanhang Yu, Huifang Deng, Wenwen Wang, Shihan Xiao, Renjing Zheng, Lianqiu Lv, Han Wang, Jianying Chen, Bo Zhang · 发表于：Clinical and Translational Medicine · 年份：2024 · DOI：10.1002/ctm2.1583 · 被引用次数：29 · 研究领域：RNA modifications and cancer、Cancer, Hypoxia, and Metabolism、Metalloenzymes and iron-sulfur proteins

Abstract Background Targeted therapy for triple‐negative breast cancer (TNBC) remains a challenge. N6‐methyladenosine (m 6 A) is the most abundant internal mRNA modification in eukaryotes, and it regulates the homeostasis and function of modified RNA transcripts in cancer. However, the role of leucine‐rich pentatricopeptide repeat containing protein (LRPPRC) as an m 6 A reader in TNBC remains poorly understood. Methods Western blotting, reverse transcription‐polymerase chain reaction (RT‐qPCR) and immunohistochemistry were used to investigate LRPPRC expression levels. Dot blotting and colorimetric enzyme linked immunosorbent assay (ELISA) were employed to detect m 6 A levels. In vitro functional assays and in vivo xenograft mouse model were utilised to examine the role of LRPPRC in TNBC progression. Liquid chromatography–mass spectrometry/mass spectrometry and Seahorse assays were conducted to verify the effect of LRPPRC on glycolysis. MeRIP‐sequencing, RNA‐sequencing, MeRIP assays, RNA immunoprecipitation assays, RNA pull‐down assays and RNA stability assays were used to identify the target genes of LRPPRC. Patient‐derived xenografts and organoids were employed to substantiate the synthetic lethality induced by LRPPRC knockdown plus glutaminase inhibition. Results The expressions of LRPPRC and m 6 A RNA were elevated in TNBC, and the m 6 A modification site could be recognised by LRPPRC. LRPPRC promoted the proliferation, metastasis and glycolysis of TNBC cells both in vivo ...