Ku70 targets BRD3-MYC/Cyclin D1 axis to drive hepatocellular carcinoma progression

Hepatocellular carcinoma (HCC) is a common cancer characterized by robustly proliferative and metastatic capabilities. Bromodomain-containing proteins are critical to the development of diverse diseases via regulating cell proliferation, differentiation, and death. However, the role of Bromodomain-containing protein 3 (BRD3) in HCC is elusive. Here, we found that BRD3 is notably upregulated in HCC samples and promotes the proliferation of HCC cells. Depletion of BRD3 notably inhibits the expression of c-MYC and Cyclin D1 and abrogates cell cycle progression in HCC cells. Co-IP and biomass spectrometry found that Ku70 interacts with BRD3 in the nucleus. The Ku70-BRD3 complex increases the expression of Cyclin D1 and c-MYC at transcriptional level in HCC. Additionally, depletion of Ku70/BRD3 ameliorates the growth of HCC xenografts established in mice. More importantly, the expression of Ku70 or BRD3 is positively correlated with the protein expression of c-MYC and Cyclin D1 in HCC samples. High expression of BRD3 or Ku70 is closely associated with poor prognosis in HCC patients. Overall, we reveal the important role of the Ku70-BRD3 complex in the onset and progression of HCC, suggesting that the Ku70-BRD3 complex is a promising target for clinical intervention in HCC.