Gut Microbiota-Derived Acetate as a Novel Therapeutic Target for Colon Cancer

Could a short chain fatty acid, usually assumed to be preventative of cancer as a group, actually be providing colon cancer fuel to grow?

Colorectal cancer is the second leading cause of cancer deaths in the US and it is accepted that environmental factors, rather than genetic factors, are mainly responsible for its development. One environmental risk factor is associated with a patient’s microbiome: there is a strong link between the amount of bacteria in a patient’s gut and the development of colorectal cancer. Gut bacteria produce short chain fatty acids (SCFAs) in the colon as dietary fibers are fermented. SCFAs include acetate, propionate and butyrate, and it is believed that SCFAs can prevent colon cancer because butyrate has been found to slow colon cancer growth. However, acetate, which is four times more abundant than butyrate in the colon, can promote breast and brain cancers, and its role in colorectal cancer is unknown.

Dr. Li has already shown that the acetate in SCFAs can serve as a carbon or energy source for colon cell growth; more importantly, he recently found that Acss2, an enzyme that converts acetate to a carbon nutrient called acetyl-CoA to support cell growth, is dramatically elevated in human colon cancer. He has further demonstrated that using drugs to block Acss2 reduces colon cancer cell growth. Because colon cancer grows rapidly and requires a large amount of energy to support its growth, Dr. Li’s prior findings have prompted him to speculate that the acetate produced by colonic bacteria provides the needed carbon nutrient to support the rapid growth of colon cancer; as such, this bacteria-generated acetate provides a druggable target for colon cancer treatment. Dr. Li will use his Fletcher Scholars Award to comprehensively test the anti-cancer efficacy of Acss2 inhibitors in several relevant colon cancer models. Because normal cells do not need Acss2 for survival, targeting Acss2 may also have the advantage of avoiding unwanted adverse side effects. Dr. Li plans to use genetic mouse models that lack Acss2 to investigate how acetate promotes colon cancer, as well as to confirm the importance of Acss2 in this process. This research challenges the belief that all SCFAs prevent colon cancer and may help identify new treatments for colon cancer that could benefit cancer patients in the future.