BRD4L cooperates with MYC to block local tumor invasion via suppression of S100A10

Targeted therapy based on BRD4 and MYC shows promise due to their well-researched oncogenic functions in cancer, but their tumor-suppressive roles are less understood. In this study, we employ a systematic approach to delete exons that encode the low-complexity domain (LCD) of BRD4L in cells by using CRISPR–Cas9. In particular, the deletion of exon 14 (BRD4–E14) results in cellular morphological changes towards spindle-shaped and loosely packed. BRD4–E14 deficient cells show increased cell migration and reduced cell adhesion. The expression of S100A10 was significantly increased in cells lacking E14. BRD4L binds with MYC via the E14-encoded region of the LCD to inhibit the expression of S100A10. In cancer tissues, there is a positive correlation between BRD4 and MYC, while both of these proteins are negatively associated with S100A10 expression. Finally, knocking out the BRD4–E14 region or MYC promotes tumor growth in vivo. Together, these data support a tumor-suppressive role of BRD4L and MYC in some contexts. This discovery emphasizes the significance of a discreetly design and precise patient recruitment in clinical trials that testing cancer therapy based BRD4 and MYC. •Knockout BRD4L-E14 or MYC promotes tumor development in vivo.•BRD4L and MYC promotes cellular adhesion.•BRD4L and MYC negatively regulate S100A10 expression.•BRD4L binds with MYC via exon 14 of BRD4L.