Now, scientists know how one gene mutation leads to skin cancer - as well as other epithelial cancers such as lung, esophagus, mouth and throat. This groundbreaking discovering may lead to the development of new treatments and clinical trials.
KMT2D, an epigenetic regulator of gene expression that is highly mutated in carcinogenesis, especially epithelial cancers, has been found to guide the renewal of epithelial tissue.
To maintain homeostasis, the epidermis undergoes routine self-renewal via stem cells in the basal layer, with dramatic alterations in gene transcription and cellular architecture. Researchers at the University of Pennsylvania, Philadelphia, discovered that KMT2D is a critical regulator of epithelial homeostasis and of p63-dependent gene expression, which has come to be known as “the master regulatory transcription factor of epithelial tissues,” they wrote in Genes & Development.
“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,” senior author Brian C. Capell, M.D., Ph.D., assistant professor of dermatology and genetics said in a prepared statement. “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.”
KMT2D plays a critical role in epithelial homeostasis by maintaining the adhesion and proliferative capacity of the epidermal basement membrane through its interaction with p63, the researchers noted.
In their research, when KMT2D was depleted from human undifferentiated epidermal keratinocytes, it resulted in reduced proliferation and premature activation of terminal differentiation genes. As a result, when grown in three-dimensional cultures, the layers of the epidermis became thickened and disorganized.
When KMT2D was depleted, it also resulted in reduced expression of p63 target genes, including key genes involved in epithelial development and adhesion.
Lin-Shiao E, Lan Y, Coradin M, et al. KMT2D regulates p63 target enhancers to coordinate epithelial homeostasis. Genes & Dev. Feb. 12, 2018. doi:10.1101/gad.306241.117