Cracking the chromatin code

Therapeutic targeting of mutant genes is a promising frontier in the fight against cancer; however, many cancers are caused by the complete loss of a gene. This is a challenge for researchers because, in those cases, the protein encoded by the gene is no longer present to be targeted. Loss of the tumor-suppressor protein SMARCB1 is implicated in rhabdoid tumors, which comprise aggressive cancers that primarily affect infants and very young children. St. Jude researchers led by Charles W. M. Roberts, MD, PhD, executive vice president and St. Jude Comprehensive Cancer Center director, were looking for a way to treat aggressive rhabdoid tumors caused by the loss of SMARCB1 when they found a new approach to treatment. 

Published in Nature, the study showed that a little-studied protein, DCAF5, is essential to rhabdoid tumors missing SMARCB1. Initially, the team identified DCAF5 as a target by using the Dependency Map (DepMap) portal, a database of cancer cell lines and genes critical for their growth. When the scientists genetically deleted or chemically degraded DCAF5, the cancer cells reverted to a noncancerous state, resulting in the sustained remission of the cancer in the mouse model. “We saw a spectacular response,” said Roberts. “The tumors melted away.” 

Normally, SMARCB1 is an essential component of a larger chromatin-regulating complex of proteins called the SWI/SNF complex. Unexpectedly, the study found that in the absence of SMARCB1, DCAF5 recognizes SWI/SNF as abnormal and destroys the complex. The researchers showed that when DCAF5 is degraded, SWI/SNF re-forms and maintains its ability to open chromatin and regulate gene expression to an extent sufficient to reverse the cancer state fully.  

“The mutation of SMARCB1 shuts off gene programs that prevent cancer. By targeting DCAF5, we’re turning those gene programs back on,” said first author Sandi Radko-Juettner, PhD, a former St. Jude Graduate School of Biomedical Sciences student, now a research program manager for the Hematological Malignancies Program.

“We have demonstrated a beautiful proof of principle,” Roberts said. “Myriad types of cancers are caused by tumor suppressor loss. We hope we have opened the door to thinking about new ways to target at least some of these by reversing, instead of killing, cancer.”

In another study, Roberts’s team again leveraged DepMap to systematically identify genes that become essential to cancer cells when SMARCB1 is absent because those genes present potential routes for future targeted therapies. 

“We discovered PHF6 as another one of those genes,” said Roberts. “We found that in healthy cells, PHF6 co-localizes with SMARCB1 and helps the SMARCB1-containing SWI/SNF complex keep chromatin open, which then becomes aberrant without SMARCB1.”

In healthy cells, SMARCB1 and PHF6 act like two-factor authentication, both of which are necessary for genes to be turned on.  Although SMARCB1 loss promotes cancer, its absence should shut down the expression of so many genes that the cell would die. When SMARCB1 is lost, PHF6 keeps many of those genes turned on, allowing the cancer cells to survive. Removing PHF6 from these cells caused cell death and slowed or stopped tumor growth, revealing a potential vulnerability to target in rhabdoid tumors and possibly other cancers.

“Twenty percent of cancers have mutations in SWI/SNF subunits,” Roberts explained. “This work on dependencies could advance the opportunity to find therapeutic interventions far more broadly than just rhabdoid tumors.”