Prof John Mariadason

In what started as a research project into colon cancer, has resulted in a major discovery that could lead to a new treatment for obesity. The study, undertaken at the Olivia Newton-John Cancer Research Institute (ONJCRI) and recently published in Nature Communications, has found that inactivating a gene called HDAC3 specifically in the intestine could protect people from diet-induced obesity.

Obesity, and eating high fat diets increases the risk of developing several types of cancer, including colon cancer. The findings from this study may therefore provide hope for some of the 12.5 million Australian adults who are overweight or obese, while also reducing their cancer risk.

In 2014, Prof John Mariadason, Head of the Gastrointestinal Cancer Program at ONJCRI, began a research study looking at the function of a specific set of proteins called histone deacetylases or HDACs in colon cancer. There are 10 HDAC genes within our bodies, and drugs targeting these proteins are currently used to treat blood cancers.

This pre-clinical study originally aimed to assess if these drugs could also be repurposed for treating colon cancer. As part of this study the researchers inactivated the HDAC3 gene in the intestine and colon of mice to assess its impact on colon cancer development.  During these studies the researchers made the remarkable finding that these mice were protected against obesity.

The normal job of the intestine is to absorb nutrients including lipids or fats, and then move these into the liver.  However, the researchers discovered that when HDAC3 is knocked out, the cells in the intestine start doing an additional job – they break down the lipids within the intestinal cells themselves.  This results in less lipid being available for uptake into the body, and ultimately, over time, in a reduction in weight gain.

On identifying this impact, Prof Mariadason expanded the study with Prof Matthew Watt, Head of Department of Physiology, School of Biomedical Sciences at the University of Melbourne; and Prof Andrew Scott, Head, Tumour Targeting Program ONJCRI, Director, Department Of Molecular Imaging And Therapy, Austin Health. It was found that mice that were fed a high fat diet, which is typical for people with diet-inducted obesity, had a significant reduction in body weight in as little as three months.

‘We have found that there is a new role for the HDAC3 gene in the breakdown of fats,’ said Prof Mariadason.

‘We know that obesity is linked to cancer and if we can block this particular gene then we could protect people from diet-induced obesity and a new obesity treatment could be delivered,’ he said.

The next phase of the obesity treatment study will focus on the delivery of HDAC3 targeting drugs specifically to the intestine, as most drugs are absorbed into the whole body rather than just one specific part.

Prof Mariadason explains, ‘We will now look for opportunities to package the drug differently so it can be delivered directly to the intestine including with the use of nanoparticles.’

The colon cancer study has also continued and findings are expected to be released in the next six months.


Publication details:

Dávalos-Salas, M., Montgomery, M.K., Reehorst, C.M. et al. Deletion of intestinal Hdac3 remodels the lipidome of enterocytes and protects mice from diet-induced obesity. Nat Commun 10, 5291 (2019).