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

Abstract

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 of RBPs in cancer using pooled CRISPR-Cas9 screening and identify 57 RBP candidates with distinct roles in supporting MYCdriven oncogenic pathways. We find that disrupting YTHDF2-dependent mRNA degradation triggers apoptosis in triple-negative breast cancer (TNBC) cells and tumors. eCLIP and m 6 A sequencing reveal that YTHDF2 interacts with mRNAs encoding proteins in the MAPK pathway that, when stabilized, induce epithelial-to-mesenchymal transition and increase global translation rates. scRibo-STAMP profiling of translating mRNAs reveals unique alterations in the translatome of single cells within YTHDF2-depleted solid tumors, which selectively contribute to endoplasmic reticulum stress-induced apoptosis in TNBC cells. Thus, our work highlights the therapeutic potential of RBPs by uncovering a critical role for YTHDF2 in counteracting the global increase of mRNA synthesis in MYC-driven breast cancers.

RETRACTED ARTICLE: N(6)-adenosine-methyltransferase-14 promotes glioma tumorigenesis by repressing argininosuccinate synthase 1 expression in an m6A-dependent manner

“…Previous studies have confirmed that the interaction of different YTH domain family proteins with m 6 A sites can have different effects on mRNA gene expression [ 33 ]. YTHDF2 can specifically recognize and bind to the single-stranded RNA sequence containing m 6 A through the YTH domain at the C-terminus, simultaneously promote co-localization with decay factors, and transport it to the P body to be degraded under the action of the N-terminus [ 34 ]. We speculate that METTL14 might inhibit the expression of ASS1 in an m6A-YTHDF2-dependent pathway, thereby promoting the occurrence and development of glioma.…”

m6A modification: recent advances, anticancer targeted drug discovery and beyond

“…YTHDF1 is reported to play a vital role in promoting translation in the cytosol, whereas YTHDF2 regulates mRNA degradation by mediating the lifetime of target transcripts [ 35 , 36 ]. Nonetheless, gene expression, cell death, and survival are associated with the YTHDF2-mediated RNA process [ 37 , 38 ]. YTHDF3 cooperates with YTHDF1 and YTHDF2 to affect the translation and decay of m6A-decorated mRNA, and inversely regulates their function [ 39 ].…”

METTL3 Is Suppressed by Circular RNA circMETTL3/miR-34c-3p Signaling and Limits the Tumor Growth and Metastasis in Triple Negative Breast Cancer

“…Jie Wu et al proposed a ten-m6A-related LncRNAs as potential biomarkers to predict the prognostic risk of TNBC (34). Jaclyn M Einstein et al found that inhibition of YTHDF2 triggers proteotoxic cell death in MYC-driven breast cancer (35). However, rarely studies reported whether m 6 A methylation contributes to cell proliferation and metastasis in TNBC, and what underlying mechanisms are involved.…”