BRD9 is an essential regulator of glycolysis that creates an epigenetic vulnerability in colon adenocarcinoma

Background: The intensive interplay between aberrant epigenetic events and metabolic remodeling represents one of the hallmarks of tumors, including colon cancer. The functions of Bromodomain Containing Protein BRD-9 in colon cancer remains indefinite. We aimed to identify the biological roles and clinical significance of BRD9 in colon cancer.

Methods: The univariate- and multi-variate Cox regression models were used to screen risk epigenetic regulators. Kaplan-Meier analysis and Pearson correlation analysis were used to assess clinical significance of BRD9. CCK-8 assays, colony formation assay, Transwell, and soft-agar assay were performed to determine the in vitro roles of BRD9. The oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) of colon cancer cells were evaluated by a Seahorse XF Extracellular Flux Analyzer. In vivo models and RT-qPCR, western blotting, and Chromatin Immunoprecipitation (ChIP) assay were conducted to explore the functional roles of BRD9 in COAD.

Results: In the study, we detected the expressions of 662 epigenetic regulators in COAD and identified a series of 42 hazard epigenetic factors with p < 0.05. Low-throughput MTT assays highlighted that BRD9 is an essential target, and targeting BRD9 could reduce significant decreases of cell growth. BRD9 overexpression could notably elevate proliferation and migration potentialities, whereas, BRD9 ablation abolished these effects. Mechanistically, functional enrichment analysis indicated the potential associations between BRD9 and glycolysis metabolism. In addition, BRD9 epigenetically coordinates the H3K27ac modifications on the promoter regions of ENO2 and ALDOC, inducing enhanced glycolysis activity. Lastly, I-BRD9 could significantly suppress the growth of colon cancer cells in vitro and in vivo.

Conclusions: Together, our study revealed previously unidentified roles of BRD9 in colon cancer metabolism and tumor progression, indicating that BRD9 could be a valuable therapeutic target for COAD patients.

 

Comments:

Summary: The study aimed to investigate the biological roles and clinical significance of the Bromodomain Containing Protein BRD-9 in colon cancer (COAD). Through various analyses, the researchers identified BRD9 as an important epigenetic regulator and a potential therapeutic target. They conducted in vitro assays, such as CCK-8, colony formation, Transwell, and soft-agar assays, which demonstrated that targeting BRD9 led to significant reductions in cell growth. BRD9 overexpression increased cell proliferation and migration, while its ablation reversed these effects. Mechanistically, functional enrichment analysis revealed a potential association between BRD9 and glycolysis metabolism. The study also found that BRD9 epigenetically regulated the H3K27ac modifications on the promoter regions of ENO2 and ALDOC, leading to enhanced glycolysis activity. Furthermore, the researchers showed that I-BRD9, an inhibitor of BRD9, significantly suppressed the growth of colon cancer cells both in vitro and in vivo. These findings suggest that BRD9 could serve as a valuable therapeutic target for COAD patients.