JHUSOM researchers uncover the oncogenic function of CHD4 in colon cancer
Described in the journal Cancer Cell and led by The Johns Hopkins University School of Medicine (JHUSOM), a study has shown that a protein that normally stops cells from transcribing faulty DNA and helps eliminate potential mutation may also have an oncogenic role in colon cancer.
The protein, called CHD4 (Chromodomain-helicase-DNA-binding protein 4)
, is a key component of the nucleosome remodeling and deacetylase (NuRD) complex. The NuRD complex is critical for developmental gene regulation, and dysregulation of NuRD can cause birth defects and diseases ranging from autism to cancer. The protein CHD4 plays an important role in epigenetic transcriptional repression.
Chronic inflammation is well established as a causative factor in many human cancers, including colitis-associated colon cancers. In inflammatory sites, high levels of nitric oxide, superoxide and other reactive oxygen and nitrogen species are generated, which can cause damage to biological molecules such as DNA. On the other hand, epigenetic changes that disrupt the regulation of gene expression prime cancer cells to spread.
For this work, the researchers identified a link between the two phenomena. To determine the role of CHD4 in DNA repair, they exposed human colon cancer cells in vitro to hydrogen peroxide, a chemical compound that induces DNA damage through the production of reactive oxygen species. They observed that CHD4 was rapidly recruited to the DNA damage sites, where it interacted with other proteins like DNA methyltransferases to silence them.
DNA methyltransferases are a group of enzymes that transfer a methyl group to DNA, a process called DNA methylation. Methylation of DNA is a common epigenetic signaling tool that cells use to lock genes in the "off" position.
When the researchers used a laser beam to cause DNA damage in colon cancer cells, they found similar results. Therefore, CHD4 and its accompanying proteins could be part of DNA repair system within cells. However, the repair team may stick around in some genes even after DNA repair is finished, which leads to the inactivation of certain tumor suppressor genes in colon cancer cells. When the researchers blocked CHD4 expression in these cells, those tumor suppressor genes lost methylation, became active, and therefore inhibited cancer spread. By accessing an available database, the researchers found that some colon cancer patients had increased levels of CHD4, and high level of CHD4 in tumor indicates poor prognosis.
Collectively, the study highlights the role of CHD4 in colon cancer. According to the corresponding author Stephen Baylin, reducing CHD4 might be a therapeutic strategy for colon cancer.