Histone serotonylation regulates ependymoma tumorigenesis

Hsiao-Chi Chen, Peihao He, Malcolm McDonald, Michael R. Williamson, Srinidhi Varadharajan, Brittney Lozzi, Junsung Woo, Dong-Joo Choi, Debosmita Sardar, Emmet Huang-Hobbs, Hua Sun, Siri M. Ippagunta, Antrix Jain, Ganesh Rao, Thomas E. Merchant, David W. Ellison, Jeffrey L. Noebels, Kelsey C. Bertrand, Stephen C. Mack () and Benjamin Deneen ()
Additional contact information
Hsiao-Chi Chen: Baylor College of Medicine
Peihao He: Baylor College of Medicine
Malcolm McDonald: Baylor College of Medicine
Michael R. Williamson: Baylor College of Medicine
Srinidhi Varadharajan: St. Jude Children’s Research Hospital
Brittney Lozzi: Baylor College of Medicine
Junsung Woo: Baylor College of Medicine
Dong-Joo Choi: Baylor College of Medicine
Debosmita Sardar: Baylor College of Medicine
Emmet Huang-Hobbs: Baylor College of Medicine
Hua Sun: St. Jude Children’s Research Hospital
Siri M. Ippagunta: St. Jude Children’s Research Hospital
Antrix Jain: Baylor College of Medicine
Ganesh Rao: Baylor College of Medicine
Thomas E. Merchant: St. Jude Children’s Research Hospital
David W. Ellison: St. Jude Children’s Research Hospital
Jeffrey L. Noebels: Baylor College of Medicine
Kelsey C. Bertrand: St. Jude Children’s Research Hospital
Stephen C. Mack: St. Jude Children’s Research Hospital
Benjamin Deneen: Baylor College of Medicine

Nature, 2024, vol. 632, issue 8026, 903-910

Abstract: Abstract Bidirectional communication between tumours and neurons has emerged as a key facet of the tumour microenvironment that drives malignancy1,2. Another hallmark feature of cancer is epigenomic dysregulation, in which alterations in gene expression influence cell states and interactions with the tumour microenvironment3. Ependymoma (EPN) is a paediatric brain tumour that relies on epigenomic remodelling to engender malignancy4,5; however, how these epigenetic mechanisms intersect with extrinsic neuronal signalling during EPN tumour progression is unknown. Here we show that the activity of serotonergic neurons regulates EPN tumorigenesis, and that serotonin itself also serves as an activating modification on histones. We found that inhibiting histone serotonylation blocks EPN tumorigenesis and regulates the expression of a core set of developmental transcription factors. High-throughput, in vivo screening of these transcription factors revealed that ETV5 promotes EPN tumorigenesis and functions by enhancing repressive chromatin states. Neuropeptide Y (NPY) is one of the genes repressed by ETV5, and its overexpression suppresses EPN tumour progression and tumour-associated network hyperactivity through synaptic remodelling. Collectively, this study identifies histone serotonylation as a key driver of EPN tumorigenesis, and also reveals how neuronal signalling, neuro-epigenomics and developmental programs are intertwined to drive malignancy in brain cancer.

Date: 2024
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DOI: 10.1038/s41586-024-07751-z

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