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Highly mutated cancer gene, KMT2D, coordinates skin tissue renewal

The protein KMT2D, a mutated gene involved in skin cancer, is also a key driver in guiding the renewal of epithelial tissues. Depleted levels of the protein in human skin cells caused undifferentiated skin cells to multiply abnormally, which can potentially lead to carcinogenesis, according to a study published in Genes and Development (Jan. 15, 2018; 32(2):181–193).

“We have known that KMT2D is one of the most frequently mutated genes in all of skin cancer, as well as other epithelial cancers such as those of the lung, esophagus, mouth, and throat,” said senior author Dr. Brian C. Capell, assistant professor of dermatology and genetics at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, in a press release. “However, prior to this study, we had no idea how those mutations caused cancer or even what KMT2D did in these tissues. Now, armed with this knowledge, I envision in the near future we may be able to test the ability of novel epigenetic drugs to reverse these deleterious mutations.”

Images show that depleted KMT2D levels cause different layers of the epidermis to become thick and disorganized (right). Photo courtesy of Perelman School of Medicine, University Pennsylvania.

Researchers observed that reducing KMT2D levels in undifferentiated human skin cells, or epidermal keratinocytes, resulted in reduced proliferation, premature spurious activation of terminal differentiation genes, and disorganized epidermal stratification. Ultimately, this led to premature differentiation of the skin tissue into a more mature, differentiated state, with different layers of skin epidermis becoming more thickened and disorganized.

These results reveal that KMT2D plays a key role in the highly coordinated process of self-renewal, proliferation, and differentiation of epithelial tissues. Specifically, the investigators observed that it maintains the operation of enhancer histone modifications H3 Lys 4 (H3K4), monomethylation (H3K4me1), and H3K27 acetylation (H3K27ac), as well as the expression of p63 target genes, including other genes involved in epithelial tissue development.

The researchers concluded that, KMT2D is needed for the maintenance of epithelial progenitor gene expression and the regulation of proper terminal differentiation.

“Our data suggests that KMT2D is critical for the proper coordination of our skin’s turnover process,” said Dr. Capell. “Because epigenetic changes are reversible, we hope that our ongoing studies in KMT2D mouse models will ultimately lead to identifying and testing new topical therapies preventing and treating skin cancer in people.”

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