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BRD4L cooperates with MYC to block local tumor invasion via suppression of S100A10
1Department of Pathogenic Biology, School of Medicine, Nantong University, Nantong 226001, China; Laboratory of Medical Science, School of Medicine, Nantong University, Nantong 226001, China.
Abstract:
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.
Insights
BRD4L and MYC suppress tumors by inhibiting S100A10. Deleting key regions of BRD4L or MYC promotes cancer growth, highlighting their complex roles in oncology.
Area of Science:
- Molecular Biology
- Cancer Research
- Genetics
Background:
- BRD4 and MYC are known oncogenes in cancer.
- Their tumor-suppressive functions are less understood.
- Targeted therapies focus on their oncogenic roles.
Purpose of the Study:
- To investigate the tumor-suppressive roles of BRD4L and MYC.
- To explore the function of the BRD4L low-complexity domain (LCD).
- To analyze the interaction between BRD4L, MYC, and S100A10.
Main Methods:
- CRISPR-Cas9 gene editing to delete BRD4L exons encoding the LCD.
- Cellular morphology, migration, and adhesion assays.
- Quantitative analysis of S100A10 expression.
- In vivo tumor growth studies.
Main Results:
- Deletion of BRD4L exon 14 (BRD4-E14) caused morphological changes, increased migration, and reduced adhesion.
- S100A10 expression significantly increased in BRD4-E14 deficient cells.
- BRD4L binds MYC via the E14 region to inhibit S100A10.
- BRD4 and MYC correlate positively in tumors, negatively with S100A10.
- Knocking out BRD4-E14 or MYC promoted tumor growth in vivo.
Conclusions:
- BRD4L and MYC exhibit context-dependent tumor-suppressive functions.
- The BRD4L-E14 region is crucial for inhibiting S100A10.
- Findings suggest careful patient selection for BRD4/MYC-targeted cancer therapies.
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