Scientists from the Australian National University (ANU) and the Peter MacCallum Cancer Centre have discovered in mice that a protein, called Menin, contributes to abnormal deactivation of specific genes in cancer cells. By targeting the Menin protein, the researchers believe they can reactivate these genes and their findings may lead to more effective treatments for lymphoma and lung cancer.
Their study is published in Nature Cell Biology in an article titled, “Targeting Menin disrupts the KMT2A/B and polycomb balance to paradoxically activate bivalent genes.”
“Precise control of activating H3K4me3 and repressive H3K27me3 histone modifications at bivalent promoters is essential for normal development and frequently corrupted in cancer,” wrote the researchers. “By coupling a cell surface readout of bivalent MHC class I gene expression with whole-genome CRISPR–Cas9 screens, we identify specific roles for MTF2–PRC2.1, PCGF1–PRC1.1, and Menin–KMT2A/B complexes in maintaining bivalency.”
“Our research discovery has major implications for many different fields of research because we need to understand how cells make decisions and change the way they act in order to find new ways to treat cancer,” explained Mark Dawson, PhD, clinician-scientist from the Peter MacCallum Cancer Centre.
ANU associate professor Marian Burr, PhD, said the researchers used gene-editing technology to delete the Menin protein from the cancer cells.
“Genetic loss or pharmacological inhibition of Menin unexpectedly phenocopies the effects of polycomb disruption, resulting in derepression of bivalent genes in both cancer cells and pluripotent stem cells,” wrote the researchers. “While Menin and KMT2A/B contribute to H3K4me3 at active genes, a separate Menin-independent function of KMT2A/B maintains H3K4me3 and opposes polycomb-mediated repression at bivalent genes.”
“Menin has been previously shown to activate genes. However, our research unexpectedly found that Menin functions to keep these genes in an inactive dormant state,” Burr said.
“This meant that by deleting Menin we could turn on the immune genes, which is essential to help the immune system to detect and kill the cancer cells.
“Importantly, specific drugs that inhibit Menin have been developed and are currently being tested in clinical trials for specific forms of leukemia.
“Our findings expand the potential clinical uses of these drugs. We have shown that Menin inhibitors can be used in combination with other existing treatments to enhance killing of lymphoma and lung cancer cells in the laboratory.
“We believe that these drugs could also be effective in other types of cancer.”
