In a study published recently in Nature Communications, a group of researchers from Ludwig Institute for Cancer Research (NY, USA) have uncovered a novel therapeutic target for glioblastoma tumors.
Glioblastoma is the most common high-grade brain tumor in adults and the most lethal type of human brain cancer. These tumors often comprise deletions and mutations in the tumor suppresor gene PTEN, which has been linked to tumor growth and chemotherapy resistance.
In this study, Ludwig researchers report a novel chromation-associated function of PTEN in complex with DAXX, a chaperone protein that helps guide the attachment of the protein H3.3 to compact looping fibers of DNA and its protein scaffolding – collectively termed chromatin.
The team demonstrated that PTEN interacts with DAXX and that by doing so PTEN directly regulates oncogene expression by affecting H3.3-chromatin binding. Frank Furnari (Ludwig Cancer Research Institute) commented: “It was an unexpected result because these are two verified tumor suppressor genes.”
First author Jorge Benitez (also Ludwig Cancer Research Institute) explained further: “We are proposing that in the absence of PTEN, DAXX competes with chromatin for H3.3, enabling the expression of oncogenes that would otherwise be suppressed. But if both PTEN and DAXX are deleted, then H3.3 is once again free to bind to the chromatin, slowing tumor growth.”
Moreover, the team demonstrated that if either PTEN or DAXX were eliminated the tumor growth occurred in experiments involving mice injected with human glioblastoma cells. However, if both genes were deleted then tumor growth slowed down.
The team believe that their findings could lead to new therapies for treating a common sub-type of glioblastoma and potentially other forms of cancer. They now plan to work out how exactly DAXX and H3.3 bind to one another.
“The next step is to design molecules that can break that complex apart by binding to DAXX,” Benitez concluded. “We think that is the first step on the way toward a therapeutic.”