Pooled CRISPR Screening Identifies P-Bodies as Repressors of Cancer Epithelial–Mesenchymal Transition

Abstract Epithelial–mesenchymal transition (EMT) is a fundamental cellular process frequently hijacked by cancer cells to promote tumor progression, especially metastasis. EMT is orchestrated by a complex molecular network acting at different layers of gene regulation. In addition to transcriptional regulation, posttranscriptional mechanisms may also play a role in EMT. Here, we performed a pooled CRISPR screen analyzing the influence of 1,547 RNA-binding proteins on cell motility in colon cancer cells and identified multiple core components of P-bodies (PB) as negative modulators of cancer cell migration. Further experiments demonstrated that PB depletion by silencing DDX6 or EDC4 could activate hallmarks of EMT thereby enhancing cell migration in vitro as well as metastasis formation in vivo. Integrative multiomics analysis revealed that PBs could repress the translation of the EMT driver gene HMGA2, which contributed to PB-meditated regulation of EMT. This mechanism is conserved in other cancer types. Furthermore, endoplasmic reticulum stress was an intrinsic signal that induced PB disassembly and translational derepression of HMGA2. Taken together, this study has identified a function of PBs in the regulation of EMT in cancer. Significance: Systematic investigation of the influence of posttranscriptional regulation on cancer cell motility established a connection between P-body–mediated translational control and EMT, which could be therapeutically exploited to attenuate metastasis formation.