The enhancer of Zeste homolog 2 (EZH2) protein promotes the development and progression of cholangiocarcinoma (CCA), found a new study published in The American Journal of Pathology. It does so through a complicated regulatory network that involves tumor-inhibiting genes, micro RNAs, and high mobility group box 1 (HMGB1). This finding supports the idea of targeting EZH2 as a therapeutic strategy for CCA.
Read more about the etiology of CCA
It was already known that EZH2 plays a role in the growth of CCA. However, its potential role in the development of the disease had not been assessed previously.
In the present study, a team of researchers led by Tong Wu, MD, PhD, from the Department of Pathology and Laboratory Medicine at Tulane University School of Medicine in New Orleans, Louisiana, investigated the role of EZH2 in CCA using a mouse model.
The researchers found that when they specifically knocked down EZH2 in the liver of the mice, the development of CCA was reduced. EZH2 knockdown also significantly reduced the progression of the disease.
The researchers then inhibited the activity of EZH2 using GSK126, which also led to a decrease in tumor burden.
“Accordingly, EZH2 depletion or inhibition reduced the growth and colony formation capability of CCA cells,” the researcher wrote.
They then identified 12 tumor-inhibiting genes that could be targets of EZH2 and showed that the protein was possibly downregulating these genes through methylation and micro RNA regulation.
Finally, the researchers have shown that HMGB1 facilitates the methyltransferase activity of EZH2, therefore playing a role in the regulation of cell growth in CCA.
EZH2 is the core subunit of a histone methyltransferase called polycomb repressive complex 2 (PRC2), which catalyzes the methylation of lysine 27 on histone H3, a histone mark that is associated with compacted chromatin and therefore repressed transcription.
Zhang J, Chen W, Ma W, et al. EZH2 promotes cholangiocarcinoma development and progression through histone methylation and microRNA-mediated down-regulation of tumor suppressor genes. Am J Pathol. Published online November 28, 2022. doi:10.1016/j.ajpath.2022.08.008