Fighting Brain Cancer Through Deletion of Tumor Suppressor Genes

Studies have shown a link between the absence of the tumor suppressor gene PTEN and the growth and treatment-resistance in glioblastoma. But scientists may have found a way to override the negative effects of PTEN deletion in a surprising way: by inhibiting a different tumor suppressor gene, DAXX.

DAXX is a so-called chaperone protein that helps guide the protein H3.3’s attachment to compact looping fibers of DNA and its protein scaffolding.

For the first time, investigators found that DAXX physically interacts with PTEN, and that PTEN regulates H3.3 loading on chromatin by limiting DAXX interactions with the histone to control the expression of tumor-promoting genes.

The findings, published in Nature Communications, indicate that the interaction can regulate oncogene expression in genes by affecting H3.3-chromatin binding.

“It was an unexpected result because these are 2 verified tumor suppressor genes,” said senior author Frank Furnari.

The investigators also conducted experiments using mice injected with human glioblastoma cells. They found that if PTEN or DAXX were eliminated, the tumor grew. But if both genes were deleted than the tumor growth slowed.

“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,” said first author Jorge Benitez. “But if both PTEN and DAXX are deleted, then H3.3 is once again free to bind to the chromatin, slowing tumor growth.”

In the animal models of glioblastoma, the investigators used genetic engineering techniques to knock out the DAXX gene, and hope to develop a drug that can provide the same results.

“The next step is to design molecules that can break that complex apart by binding to DAXX,” Benitez said. “We think that is the first step on the way toward a therapeutic.”