Inhibition of YTHDF2 triggers proteotoxic cell death in MYC-driven breast cancer

• DOI: 10.1016/j.molcel.2021.06.014
• Publication Date: 2021-07-02T14:32:16Z
• Authors: Jaclyn M. Einstein; Mark Perelis; Isaac A. Chaim; Jitendra K. Meena; Julia K. Nussbacher; Alexandra T. Tankka; Brian A. Yee; Heyuan Li; Assael A. Madrigal; Nicholas J. Neill; Archana Shankar; Siddhartha Tyagi; Thomas F. Westbrook; Gene W. Yeo
• Keywords: Adenosine; Epithelial-Mesenchymal Transition; Cell Death; Genes, myc; Mice, Nude; RNA-Binding Proteins; Breast Neoplasms; Mice, Transgenic; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays; 3. Good health; Gene Expression Regulation, Neoplastic; Mice; Protein Biosynthesis; Animals; Humans; Female

RNA-binding proteins (RBPs) are critical regulators of post-transcriptional gene expression, and aberrant RBP-RNA interactions can promote cancer progression. Here, we interrogate the function RBPs in using pooled CRISPR-Cas9 screening identify 57 RBP candidates with distinct roles supporting MYC-driven oncogenic pathways. We find that disrupting YTHDF2-dependent mRNA degradation triggers apoptosis triple-negative breast (TNBC) cells tumors. eCLIP m6A sequencing reveal YTHDF2 interacts mRNAs encoding MAPK pathway that, when stabilized, induce epithelial-to-mesenchymal transition increase global translation rates. scRibo-STAMP profiling translating reveals unique alterations translatome single within YTHDF2-depleted solid tumors, which selectively contribute to endoplasmic reticulum stress-induced TNBC cells. Thus, our work highlights therapeutic potential by uncovering a role for counteracting synthesis cancers.