Related Experiment Video
Updated: Dec 29, 2025
An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis
Published on: September 12, 2019
Targeting BET Proteins With a PROTAC Molecule Elicits Potent Anticancer Activity in HCC Cells
Huapeng Zhang1,2,3,4, Gongquan Li1,2,3,4, Yi Zhang2,5
1Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Abstract:
Background and Aim: Bromodomain and extraterminal domain (BET) family proteins are epigenetic regulators involved in human malignances. Targeting BET proteins for degradation using proteolysis-targeting chimera (PROTAC) recently has drawn increasing attention in the field of cancer therapeutics. BET proteins have been found to be overexpressed in HCC cells and tumor tissues. However, the biological activity of BET-PROTACs in hepatocellular carcinoma (HCC) remains unclear. In this study, we investigated anti-HCC activity of BETd-260, a BET-PROTAC molecule using in vitro and in vivo models. Methods: BETd-260-mediated anti-HCC activity was investigated by cell viability, apoptosis assays. Efficacy was examined with a cell lines-derived HCC xenograft model in mice. Anticancer mechanism was investigated by RT-PCR, western blotting and immunohistochemical staining. Results: BETd-260 potently suppressed cell viability and robustly induced apoptosis in HCC cells. BETd-260 reciprocally modulated the expression of several apoptotic genes in HCC cells, i.e., suppressing the expression of anti-apoptotic Mcl-1, Bcl-2, c-Myc, and X-linked inhibitor of apoptosis (XIAP), whereas increasing the expression of pro-apoptotic Bad. BETd-260 treatment led to disruption of mitochondrial membrane integrity, and triggered apoptosis via intrinsic signaling in HCC cells. BETd-260 triggered apoptosis in HCC xenograft tissue and profoundly inhibited the growth of HCC xenograft tumors in mice. Conclusion: Our data suggest that pharmacological targeting of BET for degradation may be a novel therapeutic strategy for the treatment of HCC.
Insights
BET protein degradation via BETd-260, a novel PROTAC, shows potent anti-cancer effects against hepatocellular carcinoma (HCC). This targeted therapy effectively reduces tumor growth and induces apoptosis in HCC cells and xenografts.
Area of Science:
- Epigenetics and Cancer Therapeutics
- Molecular Oncology
- Drug Discovery
Background:
- Bromodomain and extraterminal domain (BET) proteins are epigenetic regulators implicated in various human cancers.
- BET proteins are overexpressed in hepatocellular carcinoma (HCC), suggesting their potential as therapeutic targets.
- Proteolysis-targeting chimeras (PROTACs) offer a novel approach for targeted protein degradation in cancer therapy.
Purpose of the Study:
- To investigate the anti-HCC activity of BETd-260, a BET-specific PROTAC molecule.
- To evaluate the efficacy of BETd-260 in both in vitro and in vivo models of HCC.
- To elucidate the underlying anticancer mechanisms of BETd-260 in HCC.
Main Methods:
- Cell viability and apoptosis assays were performed to assess BETd-260's effect on HCC cells.
- An HCC xenograft mouse model was utilized to examine in vivo efficacy.
- Gene and protein expression changes were analyzed using RT-PCR, western blotting, and immunohistochemical staining.
Main Results:
- BETd-260 significantly suppressed HCC cell viability and induced apoptosis.
- BETd-260 modulated apoptotic gene expression, decreasing anti-apoptotic proteins (Mcl-1, Bcl-2, c-Myc, XIAP) and increasing pro-apoptotic Bad.
- Treatment with BETd-260 disrupted mitochondrial membrane integrity, triggering intrinsic apoptosis and inhibiting HCC xenograft tumor growth in mice.
Conclusions:
- Pharmacological targeting of BET proteins for degradation represents a promising novel therapeutic strategy for HCC.
- BETd-260 demonstrates significant potential as an anticancer agent for hepatocellular carcinoma.
- Targeted BET protein degradation offers a new avenue for HCC treatment development.
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...