Hepatocellular carcinoma (HCC) is the most common form of liver cancer. Whereas surgical intervention is a beneficial therapeutic strategy only for early-stage HCC patients, targeted drugs show a promising effect for advanced HCC. 

Bortezomib (BTZ), a selective proteasome inhibitor, is the first drug approved by Food and Drug Administration (FDA) for the treatment of multiple myeloma patients and has also shown promising results against liver cancer. However, like many other chemotherapeutic agents, BTZ drug resistance remains to be a major issue in the treatment of advanced HCC patients. 

A research group led by Associate Prof. CHEN Liang at the Shenzhen Institute of Advanced Technology (SIAT) of the Chinese Academy of Sciences reported a novel means to overcome drug resistance in HCC chemotherapy. This leading to a better understanding of the mechanism underlying drug resistance in HCC, which is critical for developing a more efficient strategy for advanced HCC. 

The study was published in Clinical and Translational Medicine on Jan. 21. 

The researchers constructed multiple tumor cell lines and mouse model, proved that TRIM28 activates the expression of several core subunits of the proteasome and further promoted proteasome assembly and activity. And these effects are more pronounced upon the treatment of the proteasome inhibitor Bortezomib. Mechanistically, TRIM28 enters the nucleus and binds to the promoter of various proteasome subunits, leading to increased transcriptional activation of these genes. 

They found that TRIM28-proteasome axis is the key to BTZ sensitivity in HCC cells, the suppression of this axis would bring better treatment of HCC in vitro and in vivo. In line with these observations, TRIM28 promotes the expression of proteasome subunits, BTZ-mediated cell killing in HCC tissues and poor survival of HCC patients. The TRIM28-mediated modulation of the proteasome activity would allow convenient control of the proteasome functioning and could be easily adapted for HCC therapy. 

These results defined a novel activator of the proteasome and its roles in BTZ-mediated HCC treatment, provided a potential synergistic therapeutic strategy for HCC intervention.