EZH2 inhibition as a potential therapeutic approach for multiple myeloma

Researchers from Uppsala University (Sweden) have discovered a new mechanism utilized by the EZH2 protein to promote the development of multiple myeloma. This study recently published in Oncotarget suggests inhibiting EZH2 could be a potential approach to treat the disease.

Despite the therapies available to promote the survival of patients, multiple myeloma remains an incurable disease. For this reason a research team led by Helena Jernberg Wikland (Uppsala University, Sweden) set to identify the mechanism utilized by the tumor promoting protein EZH2 in multiple myeloma.

Previously this group discovered that EZH2 was involved in histone modification and by administering EZH2 inhibitors to tumor cells, tumor survival was reduced. In this current study the team set to identify the mechanism utilized by EZH2 to promote tumor growth.

Again they treated tumor cells with an EZH2 inhibitor but this time analyzed the genes which were downregulated as a result. They demonstrated that EZH2 inhibition reduced the expression of four key oncogenes known to be involved in the development of multiple myeloma; IRF-4, XBP-1, PRDM1/BLIMP-1 and c-MYC.

Wikland commented: “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.”

This result was unexpected as normal activity of EZH2 leads to a downregulation of affected genes. Therefore by inhibiting EZH2 they anticipated an increase in the activity of these genes.

“The answer is that there are other genetic factors involved, called microRNAs. In the cells treated with the EZH2 inhibitor we found two 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”, explained Wiklund.

This study highlights the oncogenic features of EZH2. There are hopes that further studies will lead to EZH2 inhibitors as a new therapeutic alternative to current methods utilized to treat multiple myeloma.

Source: Alzrigat M, Párraga1 AA, Agarwal P, et al. EZH2 inhibition in multiple myeloma downregulates myeloma associated oncogenes and upregulates microRNAs with potential tumor suppressor functions. Oncotarget. DOI: 10.18632/oncotarget.14378