Characterizing KMT2D in Endometrial Cancer

Endometrial cancer is rising in incidence in the United States, notably among premenopausal women. This increase and the trend of delayed childbearing warrant the need for further advancement in fertility-sparing treatment for endometrial cancer. A gene left widely unexplored in its possible clinical utility as a target for fertility-sparing treatment is KMT2D, a lysine-specific methyltransferase and tumor suppressor. Preliminary gene set enrichment analysis on a 12Z endometriotic epithelial cell line identified TIMP3 as a gene that is possibly regulated by KMT2D expression. TIMP3 encodes an irreversible inhibitor of matrix metalloproteinases (MMPs), a well-recognized class of proteins as contributing to the progression of cancer. A homozygous KMT2D knockout mouse model was used to evaluate the relationship between KMT2D and TIMP3. Uteri from these mouse models underwent immunohistochemistry to determine the relative quantity of TIMP3 protein present. The results indicated that TIMP3 was present at higher levels with functional KMT2D compared to absent KMT2D, suggesting that KMT2D is responsible for regulating TIMP3 expression. These results provide insight into how KMT2D mutations mechanistically can drive the progression of endometrial cancer, and offer a potential novel target for fertility-sparing therapeutics.