The DNA strand encoding all the genetic information contained in a single human cell can be stretched out to a length of around two metres. How does a tiny cell—imperceptible to the naked eye—house such long structures? The answer is that genetic material is compacted and tightly wound around proteins called histones to form complexes known as chromatin within the cell’s nucleus.
However, chromatin not only plays an architectural role, it also acts like a molecular switch that governs how genes are expressed by changing how tightly DNA is packed. Researchers had previously identified that PBRM1 (a gene involved in regulating chromatin remodelling) is mutated in about 40 percent of all clear cell renal cell carcinomas (ccRCC), the most common type of kidney cancer.
Teh Bin Tean, Senior Principal Investigator at A*STAR’s Institute of Molecular and Cell Biology (IMCB), said that despite being discovered over a decade ago, the effects of losing PBRM1 function on chromatin remodelling during ccRCC development have remained ambiguous.
“We pursued several challenging and time-consuming approaches to get a clear picture of the role of PBRM1 in ccRCC tumorigenesis,” explained Teh, who worked with the lead author of the study and Scientist at Genentech, Xiaosai Yao, and researchers from A*STAR’s Genome Institute of Singapore (GIS); Duke-NUS Medical School, Singapore; the National Cancer Centre Singapore; KK Women’s and Children’s Hospital, Singapore; Yonsei Cancer Center, South Korea; Tisch Cancer Institute, USA; and the University of Texas MD Anderson Cancer Center, USA.
“This time, we took a molecular and epigenetic approach to study how PBRM1 mutations impact the composition and function of the whole complex,” said Teh, referring to the PBAF SWI/SNF chromatin remodelling complex which PBRM1 is a component of.
In a series of experiments using kidney cell lines (some of which had been engineered to disable PBRM1 expression), the team described PBRM1 as “the guardian of the epigenome in renal epithelial cells”. In the absence of PBRM1, PBAF complexes form in the wrong regions of the DNA, mistakenly activating the NF-kB pathway, which in turn accelerates tumour growth.
“As PBRM1 loss affects the structural composition of the complex, it consequently deviates from its original site of action and can trigger the expression of a cancer development and progression pathway,” Teh remarked.
Teh and colleagues also investigated the effects of an NF-kB inhibitor (a drug called bortezomib) and found that it can suppress NF-kB activity to delay the growth of kidney cancer with PBRM1 mutations.
Recognising the potential for targeting this pathway, the researchers are currently evaluating other types of cancer with SWI/SNF mutations to identify similar mechanisms that activate pro-tumour factors. “If this pans out to be case, our discovery and work could expand the therapeutic strategy beyond kidney cancer,” concluded Teh.
The A*STAR-affiliated researchers contributing to this research are from the Institute of Molecular and Cell Biology (IMCB) and the Genome Institute of Singapore (GIS).
