While many know that serotonin impacts mood and emotions, a smattering of studies have found that this neurotransmitter can modify histones and regulate gene expression. Now, fascinating new research reveals that histone serotonylation contributes to the regulation of aggressive brain tumors, playing a role in the complex interactions taking place between neuron–tumor signaling, epigenetics, and developmental programs.
Researchers headed by Stephen C. Mack (St Jude Children’s Research Hospital) and Benjamin Deneen (Baylor College of Medicine) built on the previously reported interplay between histone serotonylation and methylation as well as the ability of neurons to transport serotonin into astrocytes to induce histone serotonylation and modulate gene expression/regulate behavior. Now, their new study reports on how serotonergic neurons regulate the tumorigenic nature of aggressive pediatric brain tumors (ependymomas) through the gene expression-promoting effects of histone serotonylation.
Let’s hear more from Chen and colleagues on how serotonin went from boosting moods to regulating tumor progression:
- Aggressive ependymomas express genes that implicate aberrant neuronal activity in the brain microenvironment in promoting tumorigenesis as well as the SLC6A4 serotonin transporter
- Cortical excitatory neuron activity promotes ependymoma proliferation; however, the activity of serotonergic neurons in the dorsal raphe nucleus suppresses ependymoma progression
- Interestingly, ependymomas display high histone serotonylation levels (measured via the detection of H3K4me3Q5ser) compared to normal brain tissue, and blocking histone serotonylation abrogates ependymoma tumorigenesis
- This histone modification relies on serotonin transport from dorsal raphe nucleus neurons as ependymoma cells lack the relevant synthetic enzymes
- Histone serotonylation aligns with the gene expression-associated H3K27ac histone modification and enhances the expression of core developmental transcription factor genes such as LHX2, LHX4, ETV5, and KLF12
- Etv5 overexpression decreased survival in ependymoma model mice and enhanced ependymoma cell proliferation (while Etv5 knockout increased overall survival and decreased proliferation)
- Investigating this transcription factor’s role in ependymomas suggests that ETV5 promotes the deposition of the repressive H3K27me3 histone modification via polycomb repressive complex-associated protein recruitment
- This mechanism affects genes related to chemical synaptic transmission and neuropeptide signaling pathways, including the neuropeptide Y (NPY) gene – a potent modulator of neuronal activity
- NPY release from ependymomas suppresses tumor progression by promoting brain microenvironment remodeling towards increased synaptic inhibition, which suppresses brain hyperactivity and ependymoma progression
- Therefore, suppressing NPY expression via the histone serotonylation-mediated expression of ETV5 induces brain hyperactivity and ependymoma progression
Overall, this fascinating study reveals histone serotonylation as a significant regulator of aggressive pediatric brain tumor progression and provides evidence that we must explore specific interactions between neuroactive compounds, circuits, and brain tumors more deeply to improve fundamental understanding and perhaps develop specific treatment options.
“I am excited that this work has redefined our understanding of how brain tumor cells grow, and how they take advantage of factors in their surrounding environment to initiate tumors,” co-corresponding author Dr. Stephen Mack said. “I am equally excited that this work has revealed many new avenues for research that may in the future lead to new therapies, which is desperately needed for this devastating disease.”
For more on how serotonin regulates brain tumor progression by modifying histones, see Nature, July 2024.