BRD9 deregulation in liver cancer: Pathological significance and therapeutic potentials

Dr Wong, Chun Ming   (Principal Investigator (PI))

Dr Wong Carmen Chak Lui   (Co-Investigator)

Professor Ng Irene Oi Lin   (Co-Investigator)

36

2022-01-01

1500000

BRD9 deregulation in liver cancer: Pathological significance and therapeutic potentials

BRD9, Bromodomain inhibitor, Chromatin remodeling, Epigenetics, Hepatocellular Carcinoma

Others - Medicine, Dentistry and Health

08192116

Health and Medical Research Fund - Full Grant

2020

On-going

Objectives: Hepatocellular carcinoma (HCC) is the third lethal cancer worldwide. The therapeutic options of HCC patients are very limited. Bromodomain proteins are emerging as attractive therapeutic targets. Hypothesis to be tested: We hypothesize that overexpression of bromodomain-containing protein BRD9 may contribute to HCC progression. Targeting BRD9 may be a novel therapeutic strategy for HCC. Design and subjects: Expression and clinical significance of BRD9 will be evaluated in human HCC samples. Functions of BRD9 on chromatin remodeling and gene expression will be assessed in HCC cell lines. The therapeutic value of BRD9 inhibitor, I-BRD9, as a single therapy or in combination with Sorafenib or immunotherapy will be tested in mouse models. Study instruments: Gene expression will be studied by qRT-PCR and IHC. Chromatin remodeling will be investigated by ATAC-Seq. Tumor formation and metastasis in mouse models will be monitored by bioluminescence imaging. Interventions: Genetic knockout of BRD9 in HCC cell lines will be achieved by CRISPR/Cas9 system. Orthotopic tumor implantation and hydrodynamic tail vein injection will be employed to generate HCC models in immune-deficient and immune-competent mice, respectively. I-BRD9 will be used to inactivate BRD9 both in-vitro and in-vivo. Main outcome measures: The clinical significance of BRD9 up-regulation in HCC, the effect of BRD9 on chromatin remodeling, and the therapeutic potential of I-BRD9 in pre-clinical animal models will be investigated Data analysis and expected results: Statistical analyses will be used in all data analyses. We expected that this study will reveal the pathological significance and therapeutic potential of BRD9 in HCC.