Global Regulator of Gene Transcription Identified as Potential Anticancer Drug Target

The enzyme MLL1 (histone-lysine N-methyltransferase 2A) was identified as a potential target for anticancer drugs after researchers found that its inhibition prevented tumor development by shutting down the DNA damage response mechanism and suppressed inflammation by blocking the activity of proliferation-promoting genes.

MLL is a histone methyltransferase deemed a positive global regulator of gene transcription. This protein belongs to the group of histone-modifying enzymes and is involved in the epigenetic maintenance of transcriptional memory. Previous observations linked this transcription-associated methyltransferase and oncoprotein to the DNA damage response (DDR), which led investigators at the University of Pennsylvania (Philadelphia, USA) to examine the role of MLL1 in cancer development and in the appearance of age-related inflammation.


They reported in the February 1, 2016, issue of the journal Genes & Development that MLL1 displayed direct epigenetic control over pro-proliferative cell cycle genes. Inhibition of MLL1 repressed expression of pro-proliferative cell cycle regulators required for DNA replication and DDR activation, thus disabling age-related inflammation expression. However, these effects of MLL1 inhibition on age-related inflammation gene expression did not impair oncogene-induced senescence (OIS) and, abolished the ability of the age-related inflammation to enhance cancer cell proliferation. These results demonstrated that MLL1 inhibition may be a powerful and effective strategy for blocking cancerous growth through the direct epigenetic regulation of proliferation-promoting genes.

"Since tumor-promoting inflammation is one of the hallmarks of cancer, these findings suggest that MLL1 inhibitors may be highly potent anticancer drugs through both direct epigenetic effects on proliferation-promoting genes, as well as through the inhibition of inflammation in the tumor microenvironment," said first author Dr. Brian Capell, a medical fellow in epigenetics and dermatology at the University of Pennsylvania. "In cancer, this could be a potent one-two punch, by blocking both proliferation-promoting genes as well as the cancerous inflammation. One could imagine taking an MLL1 inhibitor as a primary treatment, but also as an adjuvant therapy to tamp down the rampant inflammation caused by drugs like chemotherapies."

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