multiple myeloma
Preclinical research published in Oncotarget has provided new insights regarding how the protein EZH2 affects the development of multiple myeloma (MM) and reinforces the idea that EZH2 inhibition may be a way to treat MM.
Previous research by the same group suggested that EZH2 is a potential therapeutic target in MM.
With the current study, the group further investigated the anti-myeloma mechanisms mediated by EZH2 inhibition.
They found that targeting EZH2 with an agent known as UNC1999 reduces the expression of 4 MM-associated oncogenes—IRF-4, XBP-1, PRDM1/BLIMP-1, and c-MYC.
“The role of oncogenes in the development of cancer is to potentiate the survival of the cancer cell, which, instead of undergoing cell death, as is usually the case when the cell is not functioning properly, continues to divide and proliferate,” said study author Helena Jernberg-Wiklund, PhD, of Uppsala University in Uppsala, Sweden.
“In our study, we identified 4 oncogenes that showed lower activity in cells treated with the EZH2 inhibitor as compared to control-treated cells. All 4 genes have previously been shown to be associated with the development of multiple myeloma. This confirms our previous findings that inhibition of EZH2 could be used as a means to treat multiple myeloma.”
However, the researchers were puzzled by the fact that inhibition of EZH2 could decrease the activity of the oncogenes.
The chemical histone modification performed by EZH2 leads to decreased activity of affected genes. Therefore, inhibition of EZH2 should result in a reduced level of chemical modifications, which, in turn, should result in increased gene activity.
“The answer is that there are other genetic factors involved, called microRNAs,” Dr Jernberg-Wiklund said. “In the cells treated with the EZH2 inhibitor, we found 2 microRNA genes with increased activity, and we believe that the oncogenes are regulated by these microRNAs.”
“What happens then is that, when EZH2 is inhibited, there is a reduced histone modification at the microRNA genes. This leads to an increased synthesis of the microRNAs, which, in turn, decreases the activity of the oncogenes. This is a completely new mechanism for EZH2 action.”
The microRNAs the researchers identified are miR-125a-3p and miR-320c. The team found that miR-125a-3p and miR-320c were targets of EZH2 and H3K27me3 in MM cell lines and primary cells.
The researchers said these results support their previous work suggesting EZH2 could be a therapeutic target in MM.
