From bank statements to email, computer programs use passwords to secure important information. Cellular programs also secure information in chromatin, the complex of DNA and its associated proteins. 

Cells use “biochemical passwords” comprising chemical modifications and interactions among proteins to allow or restrict access to specific genes within chromatin. St. Jude researchers are identifying how cancer cells crack the chromatin code to steal or mimic these passwords and how scientists can hack that same code to stop — or even revert — pediatric cancers.

Stealing the serotonin password for growth

Ependymoma, the third most common type of brain tumor in children, has no known effective therapeutic targets. In collaboration with Baylor College of Medicine, Stephen Mack, PhD, Department of Developmental Neurobiology, and his colleagues, engineered a mouse model of the cancer and found how aberrant neuronal activity impacts ependymoma cells by regulating pro-tumor genes wrapped in chromatin. The study, published in Nature, revealed an unexpected mechanism that may be a target for future therapies.

The research revealed that serotonin transporters are enriched within tumor cells with the ZFTA–RELA gene fusion, implying that the tumor cells forage serotonin from their environment. Serotonin was imported into ependymoma cells and attached to the histones that make up chromatin, a process called serotonylation. The presence of the ZFTA–RELA fusion protein and serotonylation allowed full access to the proliferative genes, thereby aiding tumor growth.

“Finding that histone serotonylation regulates tumorigenesis and that it’s being driven by neurons in the microenvironment is remarkable,” said Mack. “It could apply to other tumor types too.” Neuromodulatory agents, such as selective serotonin reuptake inhibitors (SSRIs), are currently used to treat certain mental health conditions. Although these agents have not been tested on brain tumors, the findings suggest they are an avenue worth exploring.

Finding that histone serotonylation regulates tumorigenesis and that it’s being driven by neurons in the microenvironment is remarkable. It could apply to other tumor types too.

Stephen Mack, PhD

Department of Developmental Neurobiology

Scientists hack cancer back

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.” 

Charles Roberts

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.

Charles W.M. Roberts, MD, PhD

Executive Vice President, Director of the St. Jude Comprehensive Cancer Center

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.”

Revealing vulnerabilities in two-factor authentication for a cell growth program

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.”

The future of chromatin research at St. Jude

The tight regulation of chromatin protects cells from carrying out potentially harmful gene expression programs while promoting the expression of protective genes, such as tumor suppressors. These fundamental processes often go awry in pediatric cancer, highlighting the tremendous opportunity to leverage chromatin control therapeutically. St. Jude scientists are well poised to continue cracking the chromatin code, finding new targeted therapies for some of the most difficult-to-treat pediatric cancers.