Stephen B. Baylin, M.D.
Johns Hopkins University
Blocking specific regions of a protein known as UHRF1 in human colon cancer cells switches on cancer-fighting genes and may impair colorectal cancer tumor growth, according to a study funded in part by NIEHS. The researchers defined specific regions of UHRF1 that establish and maintain cancer-specific DNA methylation, which refers to molecular tags on DNA that can switch genes on or off.
The researchers developed a way to block certain parts of the UHRF1 protein. They observed that two distinct segments of the protein helped the cells maintain abnormal methylation patterns: the plant homeodomain (PHD) segment and the SET and RING-associated domain (SRA) segment.
When the researchers blocked the PHD and SRA segments by inserting mutations into the regions, hundreds of cancer-associated genes became demethylated, impairing the ability of the cancer cells to divide and migrate. Using mice implanted with human colon cancer cells, they found that blocking PHD and SRA or the function of the entire protein led to smaller tumors and less spread of cancer cells. In human samples of colon cancers obtained from patients at the time of surgery, they profiled expression of UHRF1 and found an association between increased UHRF1 levels, increased promoter DNA methylation, and worse prognosis and more aggressive tumor behavior.
According to the authors, in addition to offering a potential new way to control cancers, identification of these regions on UHRF1 may also help better identify colorectal cancer subtypes, improving physicians’ ability to take a personalized approach to treatment.
Citation: Kong X, Chen J, Xie W, Brown SM, Cai Y, Wu K, Fan D, Nie Y, Yegnasubramanian S, Tiedemann RL, Tao Y, Chiu Yen RW, Topper MJ, Zahnow CA, Easwaran H, Rothbart SB, Xia L6, Baylin SB. 2019. Defining UHRF1 domains that support maintenance of human colon cancer DNA methylation and oncogenic properties. Cancer Cell 35(4):633–648.e7.