Researchers at Mount Sinai’s Tisch Cancer Institute have demonstrated the first evidence linking the tumour microenvironment to a “super enhancer” gene in colorectal carcinoma (CRC). The paper, published in Nature, could present researchers with new strategies for treating CRC.
Not so super
CRC is the second leading cause of cancer-related deaths in the US and one of the first to be studied in the context of the epigenome. “This cancer is reliant on surgery for treatment, and immunotherapies that have revolutionized the treatment of advanced cancer have only worked for a small subset of colon cancer patients. That’s why there’s a great need for novel target identification,” said the study’s first author Royce Zhou, an MD/PhD student at the Icahn School of Medicine at Mount Sinai.
In a bid to find these novel targets, the team decided to home in on super enhancers (SEs) – complex areas of DNA with high levels of transcription factor binding. These areas are central to driving the expression of genes implicated in cancer growth and progression. However, it is not clear how these SEs reprogramme cancer to drive growth.
To get a better understanding, the team used chromatin immunoprecipitation sequencing (ChIP-seq) to study the SE landscapes of 15 CRC patients. Importantly, the team had access to freshly resected CRC tumour tissue and surrounding patient-matched healthy tissue. Being able to view these live cells was crucial to understanding the underlying processes involved. “We had live specimen live cells straight from the operating room that allowed us to immediately measure the epigenetic state of that tumour,” said senior author Ramon Parsons, Director of The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai. “Without that infrastructure here at Mount Sinai, we couldn’t have made this discovery.”
The importance of the microenvironment
They discovered that one super enhancer, the PDZK1IP1 gene, was linked to CRC development and acted in response to inflammation. Previously, it was believed this gene acted as a tumour suppressor, but the authors found that in oxidative conditions it actually drives cancer growth by enhancing the reductive capacity of CRC cells via the pentose phosphate pathway.
They found that PDZK1IP1 is activated by inflammation in the surrounding tumour microenvironment (the action of inflammatory cytokines) and that this allows cancer cells to proliferate and grow. As inflammatory bowel disease is already recognised as a risk factor for CRC, this finding could aid researchers in understanding the mechanisms involved in this process.
“What this means for most patients with colon cancer is that inflammation that’s occurring in the tumour is contributing to the tumour’s growth,” said Parsons. “This stresses the importance of understanding what we can do to curb the inflammatory effects in the colon through prevention or understanding what dietary effects might have on the microenvironment in the colon.”
When PDZK1IP1 was deleted, the growth of CRC tumours slowed, providing evidence for future research into tumour-enriched super enhancer genes as novel targets for therapies. The paper also highlights the importance of conducting epigenetic profiling on patient-matched controls and primary tumour samples. “In terms of treatment, we have genetic evidence that targeting this gene actually inhibits tumours,” adds Parsons. “By understanding all these different components, we will have better tools to try to prevent the disease.”