| First Author | Einstein JM | Year | 2021 |
| Journal | Mol Cell | Volume | 81 |
| Issue | 15 | Pages | 3048-3064.e9 |
| PubMed ID | 34216543 | Mgi Jnum | J:350600 |
| Mgi Id | MGI:6741369 | Doi | 10.1016/j.molcel.2021.06.014 |
| Citation | Einstein JM, et al. (2021) Inhibition of YTHDF2 triggers proteotoxic cell death in MYC-driven breast cancer. Mol Cell 81(15):3048-3064.e9 |
| abstractText | 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 MYC-driven 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. |
